Glutaric aciduria type 1 (GA1) is an autosomal recessive disorder of organic acid metabolism due to a deficiency of glutaryl-CoA dehydrogenase (GCDH) , which is involved in the metabolism of lysine, hydroxylysine, and tryptophan (Fig. 13.2).

This leads to an accumulation of glutaric acid and 3-hydroxyglutaric acid. Part of the accumulating glutarlyl-CoA is esterified with carnitine leading to an increased ratio of acylcarnitine to free carnitine, and contributing to secondary carnitine deficiency. It has been suggested that 3-hydroxyglutaric acid, generated in the liver, and carnitine depletion, affect neuronal cell function, lead to acute striatal damage, and are responsible for the metabolic crises [6]. GA1 is caused by mutations in the GCDH gene on chromosome 19p13.2.

Glutaric aciduria type 2 (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It is caused by deficiency of electron transfer flavoprotein (ETF) and electron transfer flavoprotein dehydrogenase (ETFDH) that are normally active in the mitochondria . This interferes with the body’s ability to break down proteins and fats to produce energy. Ophthalmic involvement is not a known feature of this disorder.

GA1 was first described in 1975 by Goodman et al. in two siblings with a neurodegenerative disorder [7]. Massive glutaric aciduria was detected which increased by oral administration of lysine, and decreased by lowering protein intake. This led the authors to propose GA1 to be a disorder of lysine metabolism.

The frequency of GA1 is estimated to be 1:30,000. The prevalence is increased among the Old Order Amish of Lancaster County in Pennsylvania, and in the North American Indians in Ontario, due to founder mutation effects [8].

Affected children are generally well in the first months of life, or show only mild neurological symptoms until the first encephalopathic event , which has an average age of onset of 12 months old, and develops almost always during an infectious illness [8]. The crisis may also develop in association with fasts required for surgery, after routine immunizations, or following minor head trauma. Macrocephaly is either present at birth or develops in the first year of life, preceding the severe neurological disease. Increasing macrocephaly is often the earliest sign of GA1 [6]. The distinctive picture of a dystonic-dyskinetic and alert looking child with relatively well-preserved intellectual functions and a prominent forehead is characteristic of GA1. The predominant late clinical findings in GA1are dystonia and/or choreoathetosis (extrapyramidal signs) and spasticity. Episodes of decompensation and encephalopathy are mild or absent in approximately 25 % of affected children. These patients have mild illness with no symptoms, or may have motor delay and intellectual disability [8, 9]. Many infants have feeding difficulties because of orofacial dyskinesia. There does not seem to be any relationship between the severity of the neurological disorder and the extent of the enzyme deficiency [10]. Radiologically, the acute neurological decompensation seen in GA1 is usually accompanied by acute symmetric striatal necrosis, similar to a stroke (metabolic stroke) [6]. The mechanism by which metabolic dysfunction leads to focal brain injury in metabolic stroke is not well understood. Other radiographic findings include brain atrophy, fronto-temporal hypoplasia, white-matter disease particularly involving the basal ganglia, and internal/external hydrocephalus . It has been suggested that neuro-radiological changes may be used to identify patients with GA1 pre-symptomatically. Approximately 20–30 % have subdural effusions with or without hemorrhage [8]. Subdural hemorrhage can be the presenting feature of GA1, and may be mistakenly attributed to abusive head trauma/shaken baby syndrome [11]. A possible mechanism of acute intracranial hemorrhage in GA1 is increased fragility of bridging veins that are stretched because of cerebral atrophy (microcephalic macrocephaly). This may make the bridging veins more susceptible to rupture as a result of a short fall or other minor single acceleration-deceleration events. Widening of the Sylvian fissures with a ‘bat-wing’ appearance is a characteristic finding. Early death may occur in the course of intercurrent pneumonia and respiratory failure, during hyper-pyrexic crises or suddenly without warning.

Retinal hemorrhages are a rare manifestation which may lead to further confusion with child abuse. However, only a few intraretinal hemorrhages in the posterior pole are observed in patients with GA1 unlike the multiple, too numerous to count and multilayered retinal hemorrhages seen in child abuse [6, 12–15].

The diagnostic work-up should include urine for organic acids, plasma carnitine and acylcarnitine, fibroblast enzyme activity and/or mutation analysis. Large amounts of glutaric acid (average of 2000 μmol/kg-day) and 3-hydroxyglutaric acid (average of 2000 μmol/kg-day) are found in the urine. Repeated organic acid analyses may be necessary. While total plasma carnitine levels are consistently low, the acyl carnitine to free carnitine ration is elevated in serum and urine [6]. The enzyme deficiency can be detected in leukocytes or fibroblasts. Prenatal diagnosis is possible by analysis of amniotic fluid. GA1 has been included in the disease panels of expanded newborn screening in some areas. The presence of subdural effusion and retinal hemorrhage should also invoke a work-up to rule out possible shaken baby syndrome in the absence of clear evidence for GA1, or while studies are pending.

Early diagnosis and treatment of the asymptomatic child is essential as treatment has very little effect after the encephalopathic crisis. Treatment is by special low lysine-restricted diet containing the minimum natural protein required for growth, and carnitine and riboflavin (co-factor of GCDH) supplementation. Treatment with baclofen may be helpful for dystonia. Anti-seizure medication may be required. Surgery may be needed to remove intracranial collections of fluid and blood. A high-calorie, low- or no-protein emergency treatment protocol during acute illnesses such as infectious disease during the first 2 years of life is recommended to prevent striatal injury [16].

There are five clinical forms of 3-Methylglutaconic Aciduria (3-MGA) . Type I 3-MGA is the classic form and occurs due to an abnormality of leucine metabolism . The other types (II-V) are known as secondary 3-MGAs with the origin of 3-MGA still unclear but believed to be independent from leucine metabolism (Table 13.1) [36].

Classic, Type I 3-MGA occurs due to a deficiency of the enzyme 3-methylglutaconyl-CoA hydratase and is characterized by significantly increased urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. This branched-chain organic acid 3-methylglutaconic acid is excreted only in trace amounts in the urine of healthy individuals. Urinary excretion of 3-methylglutaconic acid in secondary (Types II-V) 3-MGA urinary excretion of 3-methylglutaconic acid is a minor finding and not the hallmark of the phenotype.

Greter et al. described a brother and sister with choreoathetosis, spastic paraparesis, dementia, optic atrophy in 1978. Urinary level of 3-methylglutaconic acid was found to be high and the excretion was increased by leucine loading [37].

Type I MGA is very rare, with only 13 patients reported in the literature as of 2003. Type III MGA has only been reported in Iraqi-Jews. The inheritance is autosomal recessive and most affected children have been the product of consanguineous marriages [38].

Type I 3-MGA is characterized by mild neurological disease (failure to thrive, psychomotor retardation, spasticity, athetosis, and delayed speech). Type II 3-MGA (Barth syndrome) is an X-linked recessive cardiomyopathy. In addition patients have neutropenia, developmental delay, short stature and typical facial features. Onset ranges from birth to adulthood. Patients with MEGDEL (3-MGA with deafness, encephalopathy, and Leigh-like syndrome) syndrome present in childhood with deafness, progressive spasticity and dystonia, psychomotor retardation and Leigh like syndrome on MRI. Type III MGA (Costeff syndrome) is characterized by a triad of 3-MGA, ataxia or extrapyramidal manifestations (spasticity, hypertonia) and optic atrophy [38, 39]. Severe neurologic symptoms develop in infancy with failure to thrive, developmental delay, and loss of milestones [38]. Adolescent onset spasticity, hypertonia, ataxia, seizures, and dyskenesis have been noted. Life span of affected patients appears to be normal. Type IV MGA has a very heterogeneous phenotype including neurologic disease, and possible cardiac, hepatic and renal involvement. Perhaps the most characteristic systemic feature of Type V MGA is the delayed onset and milder severity of neurologic manifestations which include cerebellar signs, increased deep tendon reflexes (which may be the earliest neurologic sign), and spasticity. Cranial nerves and sensation are not affected. The degree of neurologic involvement may vary between families; patients may be mildly affected or may be wheelchair bound in childhood. Intelligence is usually not affected although mild retardation may occur.

The most prominent ophthalmic finding in 3-MGA is bilateral early onset symmetric optic atrophy, particularly in type III disease [38, 39]. Optic atrophy manifests as decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Milder mutations may cause isolated onset of optic atrophy in adulthood. In type IV MGA , optic atrophy has been noted as early as 2–3 years old and may precede the onset of other neurologic signs. Optic atrophy has also been described in type I MGA [37]. Patients may also have nystagmus and in one reported case, head nodding. Decreased visual acuity may precede the diagnosis of optic atrophy . The visual acuity deteriorates early and then stabilizes at a level of 6/21–6/30. Visual evoked potential abnormalities are variable and include delayed latency or undetectable first component. The electroretinogram is normal.

The diagnostic test is detection of 3-methylglutaconic and 3-methylglutaric acid in the urine. In 3-MGA, other organic acids may also be excreted in the urine in excessive amounts. Detection of mutations in the respective genes by molecular genetic testing is confirmatory.

Treatment is supportive with involvement of a neurologist, ophthalmologist, biochemical geneticist, and physiotherapist. A possible role for coenzyme Q10 (CoQ₁₀) , the active form of ubiquinone, has been hypothesized. Use of tobacco, alcohol, and medications known to impair mitochondrial function is best avoided.

Canavan disease is a rare autosomal recessive leukodystrophy resulting in spongy deterioration of the brain. It is caused by mutations in the aspartoacylase (ASPA) gene located on chromosome 17p13.2, which leads to accumulation of N-acetylaspartate (NAA) in the brain. The pathological buildup of NAA in white matter extracellular fluid results in increased extracellular osmotic-hydrostatic pressure and initiation of the demyelination process .

Canavan disease was first described in 1931 by Myrtelle Canavan. In 1967, Hagenfeldt et al. reported cases of N-acetylaspartic aciduria in patients with leukodystrophy and progressive cerebral atrophy [40]. However, they did not link the findings to Canavan disease. In 1989, Matalon et al. found increased NAA in urine and plasma of 3 patients (2 families) of Ashkenazi descent with a diagnosis of Canavan disease [41]. Aspartoacylase was assayed in cultured skin fibroblasts from 1 patient of each family, and a profound deficiency of the enzyme was found.

Canavan disease has been reported world-wide, but is prevalent among Ashkenazi Jews, and a majority of cases with this ethnic background have two common mutations (founder effect).

Although infants with Canavan disease appear normal at birth, they develop a triad of hypotonia, macrocephaly and head lag by the age of 3–5 months. The neurologic findings are due to demyelination and leukodystrophy. Developmental delays become progressively more apparent. Most patients develop seizures, feeding difficulties, irritability, and spasticity. Life expectancy is reduced and average survival is until 10 years old. Neuroimaging shows diffuse white matter disease. There is a mild/juvenile form of Canavan disease with less severe neurological findings. These children have mild motor developmental delay and problems with speech or achievement at school. Affected individuals are usually compound heterozygotes with one mild mutation allowing for residual ASPA enzyme activity and one severe mutation. Neuroimaging does not show the generalized white matter disease seen in the severe infantile form.

Affected children are often visually impaired due to cortical visual loss. Optic atrophy and nystagmus are also common [42, 43].

Increased N-acetylasparticacid (NAA) in urine, cerebrospinal fluid (CSF) , and blood is the biological hallmark of Canavan disease. Abnormally elevated NAA may be measured quantitatively in the brain using noninvasive proton magnetic resonance spectroscopy [44]. Enzyme assays reveal reduced aspartoacylase activity in cultured skin fibroblasts. Diagnostic confirmation is obtained by molecular genetic testing of ASPA , the gene encoding the enzyme aspartoacylase. Prenatal diagnosis of Canavan disease is possible by the measurement of N-acetylaspartate in the amniotic fluid and by DNA analysis.

Treatment is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases , and protecting the airway, and physiotherapy to minimize contractures and maximize motor abilities. Seizures are treated with antiepileptic drugs. Gastrostomy may be needed to maintain adequate food intake and hydration when swallowing difficulties exist. Gene therapy for Canavan disease using recombinant AAV2 is promising and clinical trials have shown a decrease of brain NAA concentrations, with consequent behavioral and histopathological improvements, including a decline in seizure frequency [45, 46].

PKU is an autosomal recessive disorder which results from a deficiency of hepatic phyenylalanine hydroxylase (PAH) activity. This enzyme catalyzes the irreversible hydroxylation of phenylalanine to tyrosine. A defect in PAH results in hyperphenylalaninemia, as well as a deficiency of tyrosine and its metabolites—L-Dopa, dopamine, melanin, and catecholamines. Phenylalanine is converted to phenylpyruvic acid (a ketone) which is excreted in large quantities in the urine (Fig. 13.6).

The PAH gene encoding the enzyme PAH is located on the long arm of chromosome 12. Over 500 mutations in the gene are recognized which may result in abnormal enzyme variants having activity levels ranging from 0 to 70 % [47, 48]. Variable levels of severity have been classified as classic, moderate, or mild PKU, and mild hyperphenylalanemia [48]. Classic PKU is caused by a complete or near-complete deficiency of enzyme activity. Families have been reported in which both mild hyperphenylalanemia and classic PKU have affected different family members [49].

Classic PKU was first recognized by Asjbørn Følling in 1934 [50]. He recognized that a certain type of intellectual disability was caused by elevated levels of phenylalanine in body fluids. He called the condition “phenylpyruvic oligophrenia .” In the mid-1950s, it was demonstrated that patients with PKU had a deficiency of PAH activity. Guthrie introduced the concept of newborn screening for PKU in 1963 [51]. Prompted by mental retardation in his second son and a niece, he developed the Guthrie test, which facilitated population screening for PKU.

The prevalence of PKU varies in different populations, with Turks having the highest prevalence (1: 2600), followed by Irish (1:4500). The estimated prevalence in Northern Europeans and East Asians is 1:10,000. PKU is rare in Africans and Japanese with estimated prevalence of 1:100,000 and 1: 143,000 respectively. The establishment of newborn screening programs has significantly altered the natural history of the disease, and symptomatic classic PKU is now rare (1:10,00,000 live births).

The most striking effect of untreated classic PKU is profound and irreversible intellectual disability (IQ < 50). Other associated features include microcephaly, behavioral abnormalities (aggressive, hyperactive, and highly disruptive patterns), seizures, spasticity, EEG abnormalities, and MRI changes in the brain. Low levels of tyrosine, an important substrate for melanogenesis, may result in hypopigmentation of skin and hair. Patients often emanate a mousy odor due to excretion of phenylacetic acid in body fluids. Despite strict adherence to diet many patients still have some underlying sequelae and suboptimal cognitive outcome. In treated individuals, psychological problems are increased as compared to normal sibs or children [52].

A predominance of pale blue irides and blonde fundi is seen in patients with PKU [53]. Iris transillumination, foveal hypoplasia, increased incidence of strabismus, or chiasmal misrouting, all characteristics of albinism have not been reported in PKU; this is consistent with the reports of others that these patients do not have a form of albinism [53]. Visual evoked potentials are often abnormal with a significant reduction of amplitude and prolongation of latency in both untreated and treated patients with PKU [54, 55]. These changes may be seen despite the absence of visual symptoms and abnormalities on routine neuro-ophthalmological examination, indicating a high incidence of subclinical visual pathway involvement in older children and adults with PKU [54, 55]. VEP may be more sensitive than the EEG in detecting the neurological dysfunction in patients with PKU [56]. In one study, the amplitude of VEPs significantly correlated with IQ, but no correlation between VEP and dietary state and phenylalanine concentration was found [54]. Sudden onset of cortical blindness has been reported in adults with poorly controlled disease [57].

Blood phenylalanine is normal at birth in infants with PKU, but rises rapidly within the first days of life. In most Western nations, PKU is detected by newborn population screening utilizing the Guthrie card bloodspot obtained from a heel prick. Although some controversy exists about the proper timing for neonatal screening, there appears to be no significant difference between results obtained during or after the first 14 days of life [47]. Early diagnosis is most preferable. In the neonatal period, plasma levels of phenylalanine in excess of 120 μmol/L (2 mg/dL) along with phenylketones in the urine is indicative of PKU . Use of phenylalanine-to-tyrosine ratios can reduce the number of false positives. After the diagnosis has been established, predictions about the eventual phenotypic severity may be possible by characterizing the specific genomic mutation [47]. These molecular techniques may also be useful for prenatal diagnosis and carrier screening, particularly in families who already have an affected child [58].

The goal of treatment in PKU is to maintain blood phenylalanine levels within a safe target rage by restricting dietary phenylalanine. Recommended target phenylalanine levels differ among countries but majority accept 120–360 μmol/L as the target range for the first 6 years of like. This target is achieved with the use of phenylalanine-free medical formula or products soon after birth, and by restricting intake of natural protein. Care must be taken to ensure that the diet supplies all essential nutrients. The efficacy of dietary measures to maintain target range of phenylalanine is directly dependent on the severity of enzyme deficiency. Although, adherence to diet and tight monitoring of metabolic control is crucial during early childhood years, a current recommendation is to maintain a phenylalanine restricted diet for life.

Late treatment may improve visual attention span along with an improvement in behavioral patterns [59]. This finding led Giffin and coworkers to suggest that assessment of visual attention span (using a slide presentation stimulus with observation of fixation behavior) may be useful in predictive screening of older PKU individuals regarding likely overall response to late institution of dietary intervention.

Tyrosinemia type I is caused by homozygous or compound heterozygous mutation in the FAH gene, encoding fumarylacetoacetate hydrolase, the last enzyme on tyrosine degradation (Fig. 13.6).

It is predominantly associated with hepatorenal involvement without ocular sequelae. The disorder is fatal in childhood. Photophobia and sore eyes have occasionally been described in patients with tyrosinemia type I treated with nitisinone (previously known as NTBC). Nitisinone inhibits and enzyme in the tyrosine catabolic pathway and leads to marked elevation of serum tyrosine levels, and dendritiform corneal opacities have been reported as a potential consequence of nitisonone treatment [60, 61], particularly if dietary monitoring and a tyrosine-restricted diet is not appropriately followed. The lesions resolve with dietary restrictions. Tyrosinemia type III , given its rarity is less well characterized, but neurological manifestations are evident.

Alkaptonuria is an autosomal recessive disorder resulting from deficient activity of homogentisic acid dioxygenase, the third enzyme in tyrosine degradation (Fig. 13.6).

Accumulation of homogentisic acid leads to homogentisic aciduria , accumulation of homogentisic acid in connective tissue (ochronosis), and ochronotic arthritis. The homogentisate 1,2-dioxygenase (HGD) gene is located at 3q13.33 [68]

The phenomenon of homogentesic acid deposition in tissues was first described by Rudolf Virchow in 1865, and the condition was named after the yellowish (ocher-like) discoloration of tissues on histopathological examination. Alkaptonuria was one of the first “inborn errors of metabolism” described by Sir Archibald Garrod in 1908. It also has the distinction of being among the first disorders in humans shown to conform to the principles of Mendelian autosomal recessive inheritance [69].

Alkaptonuria has a frequency of 1–9/1,000,000 in the general population. The disorder is more common in Slovakia (1:19,000) [70] and the Dominican Republic [71]. In the Dominican population, the increased incidence has been shown to be consequent to a classical founder effect [71].

Deficiency of the enzyme homogentisic acid dioxygenase causes accumulation of homogentisic acid and its daily excretion in large quantities in the urine, which turns dark on standing (alkaptonuria). In urine, as in tissues, homogentisic acid oxidizes to benzoquinones, which in turn form melanin-like polymers. Accumulation of homogentisic acid and its metabolites in tissues causes ochronosis, with darkening of cartilaginous tissues and bone, arthritis and joint destruction, and deterioration of cardiac valves. Clinically and radiologically, ochronotic cartilage destruction closely imitates ankylosing spondylosis. The disabling arthritis is usually apparent by the fourth decade and continues to progress thereafter. Patients with alkaptonuria are prone to calcification of coronary arteries and cardiac valve dysfunction secondary to ochronosis [72], and kidney stones secondary to high levels of urinary homogentisic acid excretion [73].

The most common ocular finding in alkaptonuria is purple hued hyperpigmentation of the sclera which is present in over 80 % of affected patients over the age of 40 and most often located at the insertions of the extraocular muscles [74]. Dilated conjunctival vessels can be present. The ocular surface involvement is usually asymptomatic [75]. Progressive peripheral corneal thinning and astigmatism in the axis of the lesions may occur [76]. Bilateral, peripheral corneal pigmentation, in the form of discrete pinhead-sized deposits of light brown to black color [74], and increased intraocular pressure secondary to homogentisic acid deposition in the chamber angle have been reported [74, 77].

One of the earliest recognized signs of this disease is the darkening of urine when oxidized spontaneously in air. The diagnosis can be confirmed via the detection of homogentisic acid in plasma or urine through gas chromatography mass spectrometry (GCMS) . Although molecular confirmation is not required for the diagnosis of alkaptonuria, diagnosis can also be established by genetic testing of the HGD gene.

Nitisinone has been proposed as potential therapy because it inhibits the enzyme that produces homogentisic acid [73, 78]. In an international, randomized, open-label, no-treatment controlled, parallel-group study, nitisinone therapy decreased urinary homogentisic acid excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range [79]. This must be accompanied by dietary restriction of tyrosine and phenylalanine or total protein to prevent hypertyrosinemia from nitisinone therapy. High-dose vitamin C decreases urinary benzoquinone acetic acid but has no effect on homogentisic acid excretion. Surveillance for cardiac, renal, and prostate complications after the fourth decade of life and strict attention to pain control is advisable.

Classic homocystinuria is an autosomal recessive disorder related to the deficiency of cystathionine β-synthase enzyme and the subsequent accumulation of homocysteine, homocysteine disulfide metabolites (homocystine and homocysteine-cysteine) and methionine (Fig. 13.8a, b).

Cystathionine β-synthase enzyme is encoded by the CBS gene on chromosome 21q22.3, the only gene responsible for classic homocystinuria [80]. Other metabolic disorders characterized by elevated homocysteine include deficiency in methylene-tetrahydrofolate reductase (MTHFR) , an enzyme that catalyzes the transformation of homocysteine to methionine via the remethylation pathway, and defects in methylcobalamin synthesis, the cofactor for methionine synthase enzyme. These disorders lead to hyperhomocystinemia , and ocular features of classic homocystinuria. They do not have the characteristic systemic features of classic homocystinuria and are characterized by low methionine levels.

Classic homocystinuria was first recognized in 1962, during a survey for metabolic disorders in institutionalized mentally impaired inmates in Northern Ireland. The aminoaciduria was detected using urine chromatography and ectopia lentis was noted. The discovery of cystathionine β-synthase deficiency as a causative enzymatic deficiency followed shortly thereafter [81]. In 1964, Gibson reported the association with thromboembolic complications and the confusion with Marfan syndrome owing to the presence of skeletal abnormalities and ectopia lentis [82]. Spaeth and Barber demonstrated that some patients with homocystinuria respond to pyridoxine (vitamin B₆) [83].

Classic homocystinuria has a worldwide prevalence of 1:335,000 live births, while in Ireland it is higher at 1:65,000; [84] the prevalence in Qatar is believed to be the highest at 1:1800 [85]. Skovby and colleagues observed that the number of individuals identified with homocystinuria with homozygosity for the widespread c.833T>C (p.I278T) mutation in the CBS gene fall far short of the number of such individuals expected on the basis of the heterozygote frequency for this mutation in Denmark. They concluded that prevalence is underestimated as patients could be potentially missed by both newborn screening and clinical ascertainment [86].

Patients with classic homocystinuria are normal at birth but in about 60 % of patients, variable degrees of developmental delay and cognitive disability become evident with time. Other neurological findings include seizures and psychiatric disturbances. Patients develop Marfanoid habitus with tall stature and thinning and elongation of long bones (Fig. 13.9a). Osteoporosis is a major complication and predisposes patients to scoliosis, pathological fractures, genu valgum, and pectus carinatum or excavatum. They often have fair complexions and a malar reythematous skin eruption . They may have premature greying of the hair, particularly in the temples

Thromboembolism of large and medium-sized vessels is a major cause of early morbidity and mortality. Thrombophlebitis and pulmonary embolism are common, however, thrombosis of the carotid and renal arteries is a frequent cause of death. Most thrombotic events are precipitated by venous stasis, for example during general anesthesia. The thrombosis is due to a platelet aggregation defect.

Homocystinuria due to MTHFR deficiency is characterized by progressive neurological involvement. The manifestations range from mild to aggressive. Neonates may have seizures, failure to thrive and early death from neurological complications, but some affected patients may live to adulthood without symptoms . Risk for serious thromboembolic events is similar to classic homocystinuria [87, 88].

Untreated, 90 % of individuals develop progressive ectopia lentis by 5–10 years of age, with the lens typically subluxating inferiorly, although any direction may occur [89–92]. This has been attributed to altered functional properties of zonular fibrillin-1 and tropoelastin by homocysteinylation [93]. Slit-lamp examination of patient reveals broken zonules, in contrast to Marfan syndrome where the zonules are stretched, but intact (Fig. 13.9b).

As the lens becomes increasingly subluxed, the patient will experience increasing optical blur and distortion related to spherical aberrations and astigmatism from the lens edge becoming coincident with the visual axis and tilting of the lens [91]. Eventually, the aphakic visual axis may yield the best corrected vision. In addition, patients experience markedly increasing lenticular myopia due to an increase in the refractive power of the lens which becomes more globular (increased anterior-posterior diameter) from zonular breakage and dehiscence. However, increasing myopia may occur in the absence of frank ectopia lentis in untreated patients [92]. Complete recurrent anterior dislocation of the lens into the anterior chamber associated with intermittent elevation in intraocular pressure either due most often to pupillary block is commonly seen in patients with homocystinuria. This is particularly problematic in children as the vitreous is well attached to the posterior lens surface allowing it to move forward with the lens through the pupil, with subsequent “strangulation” by the encircling pupil once subluxation is completed. Other ophthalmic features of this condition include cataract , iris atrophy, retinal detachment, central retinal artery occlusion, optic atrophy, anterior staphylomas, and corneal opacities. Iris atrophy may be due to iris ischemia from recurrent high intraocular pressure or thromboembolism of iris vessels [91]

Plasma amino acid profile typically illustrates the increase in methionine, homocystine, and cysteine-homocysteine disulfide with concomitant low cystine and cystathionine. Plasma total homocysteine is an important marker of the disease with typical levels exceeding 200 μmol/L in CBS deficient patients (normal less than 15 μmol/L). Methionine levels decrease with age and may normalize in older patients , a factor that may confuse CBS deficiency with other disorders associated with elevated homocysteine. Measurement of cystathionine ß-synthase activity in cultured fibroblasts is the key for definitive diagnosis although sequence analysis of CBS gene has a mutation detection frequency of >95 % [94]. Prenatal testing is possible through measurement of cystathionine ß-synthase activity in cultured amniocytes (but not in chorionic villi because this tissue has very low activity of the enzyme), measurement of total homocysteine in cell-free amniotic fluid, and molecular genetic testing if both disease-causing alleles of an affected family member have been identified. Blood methionine levels have been used for neonatal screening programs. False negatives may occur in pyridoxine responsive patients, breast fed babies, or individuals on low protein diets [92].

Several studies have shown that early diagnosis and institution of treatment and dietary restriction slows the progression of disease in homocystinuria and reverses some of the features. Treatment lessens the risk of thrombosis and influences the progression of central nervous system damage. Patients with homocystinuria may be divided into pyridoxine-sensitive and pyridoxine-insensitive groups. Forty percent of individuals respond to high doses of vitamin B6, and for them pyridoxine , folic acid and vitamin B-12 are prescribed. Additional agents for vitamin B6 non-responders include oral Betaine which remethylates homocysteine to methionine and may be effective therapy to help lowering homocysteine level. Vitamin C supplementation is often used to ameliorate endothelial dysfunction and in turn to lower the risk of atherothrombotic events. Dietary restriction of methionine and cysteine supplementation can prevent lens luxation and learning disability in majority of patients with reported normal IQ in pyridoxine non-responsive patients treated since birth [95]. Treatment is aimed at maintaining the plasma methionine, homocystine and cystine within the normal range and the plasma homocysteine concentration as close to normal as possible.

Medical management of complete lens subluxation may include pharmacologic mydriasis in the supine position, allowing the lens to drift back behind the pupil, followed by acute and chronic pharamacologic miosis [91]. If the lens does not drift back on its own, manual compression of the cornea either with a finger or cotton swab may help the lens to reposition. Peripheral iridectomy has been tried in an effort to prevent pupillary block. Yet, recurrent subluxation usually occurs even with successful medical management [91]. In these cases, and in cases where mental retardation prevents easy medical management, surgery is recommended [91]. Surgical management of ectopia lentis in patients with homocystinuria raises two concerns: ocular risks and general anesthetic risks . Ocular risks include vitreous loss, retinal detachment, and the loss of lens material into the posterior segment of the eye. Anesthesia can be complicated by thromboembolic events in the intra- or perioperative period, and precautions should include maintenance of homocysteine to near normal levels, aggressive hydration (fluid at 1.5 times maintenance with close monitoring to avoid fluid overload), and prophylaxis for deep vein thrombosis during and after surgery . Rotating limb-to-limb compression bandages can assist with venous return during surgery. General anesthesia may also be complicated by hypoglycemia secondary to hyperinsulinemia, and intraoperative monitoring of glucose levels has been advocated in patients with homocystinuria undergoing general anesthesia [96]. Given the anesthetic risks , bilateral, simultaneous lens extraction under a single anesthetic should be considered. Due to the broken zonules, the lens may be very loose, requiring a posterior approach, perhaps with perfluorocarbon used to float the lens forward. With appropriate anesthetic precautions and modern microsurgical techniques , the risks associated with the surgical management of ocular complications of homocystinuria are reduced. Correction of the aphakia with glasses or contact lenses is the safest method of visual rehabilitation [97].

Sulfite oxidase catalyzes the last step of conversion of sulfite to sulfate in the degradation of sulphur containing amino acids including cysteine, an essential component of lens zonules. Sulfite can also be metabolized by other route to thiosulfate or S-sulfocysteine (Fig. 13.10).

Molybdenum cofactor is required for sulfite oxidase and there is thus an overlap with the phenotype of molybdenum cofactor deficiency. Sulfite oxidase deficiency is caused by mutations in the SUOX gene (12q13.2).

Mudd et al. found increased sulfite in the urine and decreased inorganic sulfate excretion in an infant with neurological disease and ectopia lentis. Sulfite oxidase deficiency was postulated [98].

Less than 100 cases of this autosomal recessive disorder have been reported.

This disorder is nearly always fatal in childhood. It is characterized by early onset of intractable seizures, often in the neonatal period, severe psychomotor retardation, failure to thrive, microcephaly, hypotonia passing into hypertonia, and early death. Neuroimaging may reveal gross cerebral atrophy affecting virtually every part of the brain, cystic changes, demyelination, and calcification.

The major manifestation is ectopia lentis although strabismus, nystagmus, non-reactive pupils, cortical visual impairment, and optic atrophy may also be observed [99, 100]. The direction of ectopia lentis is non-specific [100].

Not all patients have ectopia lentis in infancy. As in homocystinuria, zonules are broken rather than stretched.

Urinary excretion with elevated blood levels of inorganic sulfite, thiosulfate, and S-sulfocysteine are diagnostic. The absence of xanthinuria distinguishes isolated sulfite oxidase deficiency from molybdenum cofactor deficiency, in which urate levels are low, with xanthinuria. Molecular genetic testing is confirmatory. Prenatal biochemical or genetic testing is available.

Dietary restrictions of cysteine and methionine may be useful [101]. But most children are so severely affected at diagnosis that this is not helpful.

Molybdenum is required as a cofactor by enzymes sulfite oxidase, xanthine oxidase, and aldehyde oxidase. Sulfite oxidase is the terminal enzyme in the metabolism of sulfur containing amino acids (Fig. 13.10) and also has a role in detoxifying exogenous sulfur dioxide and sulfite. The other two enzymes are involved with purine degradation which produces uric acid production. The major clinical manifestations of molybdenum cofactor deficiency (MOCOD) are due to decreased activity of sulfite oxidase. MOCOD is usually caused by mutations in the MOCS1 gene located in chromosome 6p21.3 [102, 103]. Other genes implicated in causing MOCOD when mutated are MOCS2 (5q11), and GPHN (14q23).

MOCOD was first reported in 1978 in a neonate who presented with feeding difficulties, severe neurological abnormalities, ectopia lentis and dysmorphism. Combined deficiency of xanthine oxidase and sulfite oxidase was detected. Serum molybdenum concentration was normal [104]. Subsequent studies on the same patient in 1980 led to recognition of molybdenum cofactor deficiency as underlying pathology. Molybdenum was absent in the liver sample despite normal serum levels of the metal; however, the active molybdenum cofactor was not detectable in the liver [105].

The condition is estimated to occur in 1 in 100,000–200,000 newborns worldwide. More than 100 cases have been reported, although it is thought that the number of affected individuals may be higher, as many patients die in early neonatal period without a diagnosis.

Babies are normal at birth, but within a week develop severe, intractable seizures and feeding difficulties with failure to thrive. Growth delay, axial hypotonia with peripheral hypertonia, opisthotonos, and developmental delay are seen due to toxic accumulation of sulfite in the brain. Death occurs in the first decade, usually between 2 and 6 years of age [106]. CT scan may show brain atrophy and ventriculomegaly [107]. Urinary xanthine stones are the only manifestation of the xanthine oxidase deficiency. Other minor findings include dysmorphism (redundant skin folds, coarse facies, frontal bossing, bitemporal narrowing, long philtrum, high palate, pectus carinatum, and scoliosis), kidney malformations and hip dysplasia. Some children have an exaggerated startle reaction (hyperekplexia) to unexpected stimuli such as loud noises.

Ectopia lentis plays an important role in establishing diagnosis. Although often present in the first few years, frank ectopia may be preceded by several years of symmetric spherophakia due to abnormal zonular fibers [107]. Mild ectopia lentis may even be detected in infancy. Although direction of the lens is variable, down going is the most common. Nystagmus , visual impairment due to cortical visual loss or optic atrophy, enophthalmos and esotropia have also been reported.

The biochemical profile includes hypouricemia, low urinary excretion of sulfate and urate, and increased serum xanthine, sulfite, and S-sulfocysteine. Urine sulfite screening tests are insufficient for diagnosis as false negatives may occur. Prenatal diagnosis by enzyme assay and genetic analysis chorionic villus samples has been described [108].

Currently, there is no known therapy for MOCOD. Anecdotal reports of successful treatments include the administration of cyclic pyranopterin monophosphate, an intermediate in molybdenum biosynthesis [109], NMDA N-methyl-d-aspartate receptor inhibition with dextromethorphan, thiamine and cysteine supplementation and methionine-restricted diet [110].

Gyrate atrophy is a rare, autosomal recessive disorder caused by deficiency of the pyridoxal phosphate-dependent, nuclear-encoded, mitochondrial matrix enzyme ornithine delta-aminotransferase (OAT), leading to markedly elevated ornithine levels (10–15-fold) in plasma and other body fluids (Fig. 13.11).

Gyrate atrophy is caused by mutations in the OAT gene on chromosome 10q26 [119, 120].

Although the first clinical description of the gyrate atrophy of the choroid and retina may date back to 1888, it wasn’t until 1895 and 1896 that two ophthalmologists, Cutler and Fuchs recognized it as a distinct clinical entity. It took 85 years after the initial clinical description for the association with hyperornithinemia and ornithinuria to be recognized [121, 122]. In a routine examination of the urinary amino acids of an 8 year old boy who had choroidal degeneration of unknown etiology, an enlarged lysine-ornithine spot was found on the urine high-voltage electropherogram. Subsequent two-dimensional thin-layer and automatic ion-exchange column chromatography indicated that the spot was ornithine. The plasma ornithine concentration was ten times higher than normal, although the levels of other plasma amino acids were normal. The ocular changes were diagnosed as gyrate atrophy of the choroid and retina, and the diagnosis was confirmed by electroretinography [121]. Subsequently, in 9 patients with gyrate atrophy of the choroid and retina, plasma, urinary, CSF, and aqueous humor ornithine concentrations were found to be 10–20 times higher than controls [121].

The incidence of gyrate atrophy is less than one in 1,000,000, except in Finland, where the estimated frequency of gyrate atrophy is about 1 in 50,000 individuals with an estimated frequency for heterozygotes of 1 in 110 individuals [123].

Aside from visual impairment, patients with this condition are generally asymptomatic. Rarely, systemic signs may occasionally be seen including mild proximal weakness, mild developmental delay, cerebellar signs, and hypotonia. Brain MRI demonstrates early degenerative and atrophic changes and electroencephalogram (EEG) abnormalities may be seen [124]. Skeletal muscle biopsy shows marked abnormalities, including fatty degeneration and muscle fiber atrophy, which are out of proportion to the clinical muscle signs [125, 126]. Non-specific morphological abnormalities of the mitochondria have also been described [122]. Patchy alopecia and scaling of the scalp and skin with areas of localized hypopigmentation has been described [126].

Patients typically report night blindness, loss of peripheral vision, or both by 10 years of age. On fundoscopy, sharply demarcated, circular areas of chorioretinal atrophy distributed around the peripheral fundus are observed that, later in the disease process, coalesce and spread posteriorly. The atrophic areas have a characteristic scalloped leading edge (Fig. 13.12a).

The macula and, central vision are often preserved into the fourth or fifth decade of life [127]. The retinal degeneration may be accompanied by vitreous syneresis, retinal vessel attenuation, loss of the retinal reflex, and mottling of the RPE. Axial moderate to high myopia with astigmatism can be seen in early childhood. Posterior subcapsular cataracts usually begin in the late teens, and fully developed posterior subcapsular cataracts with diffuse cortical opacities are almost invariably present by age 30.

Intraretinal cystoid spaces and hyper-reflective deposits in the ganglion cell layer may be demonstrable by spectral-domain optical coherence tomography (OCT), and fundus autofluorescence imaging may reveal abnormalities in areas that appear ophthalmoscopically intact (Fig. 13.12b) [128].

Elecroretinogram (ERG) shows reduction in rod and cone parameters early in the course of the disease, and may be undetectable in later stages of the disease. Electro-oculogram (EOG) reduction parallels the reduction in the rod ERG. Dark adaptation shows markedly elevated rod thresholds in areas of field corresponding to involved retina.

The pathophysiology of gyrate atrophy remains unclear, but has been attributed to direct toxic effect of high plasma ornithine concentration, reduced availability of proline [129], and deficiency of the energy-carrying phosphocreatine pool due to impaired creatine synthesis [130]. The fundus picture of gyrate atrophy can appear in the presence of normal ornithine levels; gyrate atrophy in this situation should raise the suspicion of another metabolic disorder iminoglycinuria, which is characterized by proline deficiency [129, 131, 132].

The biochemical hallmark of GA is hyperornithinemia with levels that are 10–15 times normal (400–1400 μM). Urine amino acids show evidence of spill-over ornithinuria. Ammonia, and plasma glutamine are normal, and urine has no detectable homocitrulline. These three features distinguish gyrate atrophy from hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome . Urine orotic acid excretion is also increased in HHH syndrome. High levels of ornithine also act as a feedback inhibitor on glycine transamidase which plays a role in the generation of creatine, with resultant low creatine levels. The diagnosis of gyrate atrophy can be confirmed by measurement of OAT enzyme activity in skin fibroblast or lymphocytes. In addition to the importance for counseling, defining the causative mutations may be helpful prognostically [120]. Degree of expression of the OAT gene and OAT enzyme synthesis has been linked to degree of pyridoxine responsiveness in patients with gyrate atrophy [133]. Prenatal diagnosis by estimating OAT enzyme activity in amniotic fluid is available [134].

If started at an early age, long-term substantial reduction of plasma ornithine levels may appreciably slow the progression of the chorioretinal disease and, to a lesser extent, the progressive loss of retinal function [135, 136]. A number of general approaches to therapy have been explored, including stimulation of residual OAT enzyme activity with pharmacologic doses of pyridoxine, reducing intake of arginine (the precursor of ornithine), and creatine and/or proline supplementation. Restriction of arginine has been shown to slow the development of retinal lesions in animal and human studies [135–138]. Among Finnish patients, less than 5 % have been reported to be responsive to pyridoxine (vitamin B6), a cofactor for OAT activity, with reduction in plasma ornithine levels [139]. The frequency of pyridoxine-responsive gyrate atrophy in other populations is unknown. A 2-week trial of pyridoxine therapy (300–600 mg/day) is recommended for all newly diagnosed patients to determine their responsiveness [140]. Creatine supplementation has been tried in some patients based on the hypothesis that creatine deficiency plays a role in the pathogenesis of the disease Management. Although it may stabilize the occasional reported skeletal muscle abnormalities, progression of the chorioretinal degeneration was not prevented [141]. Deficiency of local retinal proline synthesis has been hypothesized to play a role in the chorioretinal degeneration [142], and proline supplementation may slow the progress of retinal degeneration in some patients [135].

LHON is characterized by acute and painless central vision loss of both eyes in a sequential fashion over a period of days to months [197]. All identified mutations, are located within mitochondrial DNA (mtDNA) genes encoding subunits of complex 1 of the respiratory electron transfer chain implying that LHON is primarily related to complex 1 dysfunction with subsequent decreased ATP production and elevated levels of oxidative stress [198]. Several point mutations in the mitochondrial genome have been identified in patients with LHON, but over 95 % of individuals with LHON have one of three ‘primary’ LHON point mutations in mtDNA: m.3460G>A in the ND1 gene (13 %), m.11778G>A in the ND4 gene (69 %), or m.14484T>C (14 %) in the ND6 gene [199]. Secondary LHON-associated mtDNA mutations prevalent in the general population that have been identified at higher frequencies in patients with LHON include m.4216T>C, m.13708G>A, and m.15257G>A [200]. Although inheritance is always maternal, incomplete penetrance, variable expression and a predilection for males are well known. Male predominance has been attributed to existence of an X-linked susceptibility gene acting in synergy with the mtDNA mutation to precipitate visual loss. Approximately 50 % of males with an LHON mutation will develop disease while only 10 % of females become affected [201]. This has been attributed to the presence of modifier mutations or polymorphisms located on the nuclear and mitochondrial genomes . Various environmental modifiers have been investigated with tobacco smoking and alcohol intake being the most identified risk factors [202]. Kirkman et al. found a strong association between visual loss and smoking that was independent of gender and alcohol intake [203]. Genotype-phenotype correlation is established in LHON. LHON patients carrying m.11778G>A mutation have the least visual recovery, those who carry the m.14484T>C mutation have the greatest visual recovery and the m.3460G>A mutation carriers are in between [204–206]. Age of onset is another prognostic indicator as early age of onset of visual loss is associated with better visual outcome [207].

LHON was first described by Theodor Leber in 1871. Erickson in 1972 noted that LHON is maternally inherited. In 1980 Gilles et al. explained that there is cytoplasmic transmission of a genetic error in the mitochondrial genome [208]. In 1988 Wallace reported the 11778G>A mutation [209].

An epidemiological study in North England indicated that LHON is the most frequent mitochondrial disorder and estimated the prevalence of LHON in that population to be 1 in 31,000 [201]. Two other studies from Holland and Finland showed prevalence of 1 in 39,000 and 1 in 50,000 respectively [210, 211]. In Australia, it was estimated that 2 % of optic atrophy is due to LHON [212].

Although LHON is primarily an ocular disease, LHON plus syndrome occurs when LHON is accompanied by asystemic presentation. Cardiac arrhythmias and neurological abnormalities are among the main associations. Peripheral neuropathy, myopathy, dystonia, and myoclonus have been reported in LHON patients [213, 214]. Genotypic –phenotypic association has been observed in LHON plus syndromes where systemic involvement occurs with specific mtDNA variants such as m.44160T>C, m.1169A>G, m.14596tT>A, and m.14459G>A [205, 215]. An overlap of systemic presentation between LHON and MELAS has been observed in patients carrying two point mutations affecting the respiratory chain complex I activity namely m.3376G>A and m.3697G>A [205].

Harding et al. 1992 described a combination of LHON and demyelinating disease in a female carrying the m.1178G>A mutation [216]. Similar observation was shown later on more female patients with MRI findings of periventricular white matter lesions and oligoclonal band in CSF resembling MS were found in these females after the onset of visual loss [217].

The clinical presentation of LHON can be divided into three phases; the pre-symptomatic phase, the cute phase and the chronic phase [201]. In the acute phase, the patient usually presents with acute onset painless loss of central vision that becomes worse over a period of 4–6 weeks. Both eyes are involved at the onset in about a quarter of cases and the other eye will follow and become affected within the next 6–8 weeks in the remainder. Rare cases of unilateral LHON have been reported in literature. The majority of patients present in the second or the third decades of life and by the age of 50 years, 90 % of patients carrying the LHON mutation will experience visual dysfunction [201, 210]. The visual acuity loss may be to less than 6/60 and patient will have either dense central or cecocentral scotomas. The pupillary reaction is often normal compared to the extent of the visual loss. The fundus will show typical vascular tortuosity of the central retinal vessels, retinal nerve fiber layer swelling and circumpapillary telangiectatic microangioapathy [206]. Twenty percent of patients with LHON might have normal looking optic discs [201], and retinal nerve fiber layer (RNFL) edema without leakage on fluorescein angiography . The angiographic picture and the RNFL swelling can be present in asymptomatic female carriers [218]. Abnormal color discrimination along the blue-yellow axis, minor visual field defects, reduced contrast sensitivities and abnormal visual evoked potential have been reported in this phase as well [201]. Approximately 6 weeks from the acute phase, the optic disc becomes pale with the temporal side being usually more affected as a result of nerve fiber loss along the papillomacular bundle. In the chronic phase, optic disc cupping will be apparent reflecting severe retinal ganglion cells loss and the chronicity of the LHON [199].

Following LHON acute attacks, patients suffer severe and permanent visual impairment with minimal improvement of vision thereafter. The end point of LHON is atrophic optic nerve with persistent visual acuity and field’s loss. The pupillary reaction is spared in LHON [199].

Spontaneous recovery has occasionally been reported in patients with LHON [207, 219].

The clinical presentation is usually typical and may be supported by family history consistent with maternal inheritance. Up to 40 % of patients have no family history. Diagnosis is established by the identification of the disease-causing mutation through targeted mutation analysis for known LHON mutations or whole mtDNA genome sequencing. The fact that 85–90 % of patients with LHON harbor homoplasmic mutations makes analysis of DNA extracted from peripheral blood highly sensitive.

LHON was until very recently considered an untreatable disease. Recent clinical data with redox-active electron carriers have demonstrated that protection and even recovery of vision may be a possibility. Use of the coenzyme Q10 derivative, idebenone, continues to show evidence as a possible treatment for LHON patients although results have not been entirely consistent. Klopstock et al. had shown through a placebo-controlled, randomized, double-blind study that a dose of 900 mg daily of idebenone resulted in protection against loss of vision and improvement of visual acuity. The treatment effect persisted even 30 months after termination of treatment [220]. Another compound that is being currently investigated as a promising antioxidant agent is α-tocotrienol-quinone (EPI-743) [221]. Gene therapy clinical trials either to introduce the defective gene or entire complex 1 are underway. Preclinical data of the ex– and in-vivo expression of the wild-type form of the ND4 gene using AAV vectors are promising and hopefully may change the natural history of the disease.

Autsomal dominant optic atrophy (ADOA) is characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity usually between ages 4 and 6 years, visual field defects, and color vision defects [222]. There are at least four known nuclear loci and three identified genes related to the disease with OPA1 gene being the gene responsible for the 50–60 % of familial cases. OPA1 encodes for a transmembrane protein embedded within the mitochondrial inner membrane. When mutated it results in mitochondrial fragmentation, mitochondrial dysmorphism with balloon like enlargement and disorganization of cristae, with para-crystalline inclusion bodies. OPA1 mutations have also been detected in patients with AD-hereditary spastic paraplegia (HSP) and patients with visual loss and MS-like illness. Poor visual prognosis is observed among those with DOA plus variants. This indicates that OPA1 mutation may not only target the RGC but also extraocular muscles, skeletal muscles and other neural tissues [201]. The gene for type 2 optic atrophy (OPA2) is located on the X chromosome and hence is not included with ADOA despite the clinical similarity. The gene which causes OPA3 encodes for a mitochondrial protein that has been associated with autosomal recessive optic atrophy, premature cataract, and 3- methylglutaconic aciduria. Other loci OPA4-6 are known but the genes have not been cloned.

ADOA was first described clinically by Batten in 1896 and named Kjer’s optic neuropathy in 1959 after Danish ophthalmologist Poul Kjer, who studied 19 families with the disease. In 2000 a protein encoded by the nuclear gene OPA1 was identified as the cause of ADOA [222].

The prevalence of ADOA in north England is 1 in 35,000. The estimated prevalence of OPA1 is 1:50,000 in most populations, 1 in 35,000 in Northern England or as high as 1:10,000 in Denmark.

OPA1 disease may also involve neuromuscular manifestations in up to 20 % of patients due to secondary impairment of mitochondrial respiratory chain complex IV. In a multicenter study performed by Yu-Wai-Man et al. 2010, bilateral sensorineural deafness in late childhood to early adulthood was the most frequently observed extraocular feature of ADOA [223]. They noted also that ataxia, myopathy, peripheral neuropathy and progressive ophthalmoplegia (PEO) also developed from the third decades in those patients.

ADOA patient usually presents with gradual loss of vision occurring in the first or second decades of life.

The visual acuity is variable, ranging from 6/6 to hand motion. Later progressive loss of vision is seen in 50–75 %. Most of the patients will have generalized dyschromatopsia. The primary defect in ADOA is in the papillomacular bundle which will result in central, centrocecal and paracentral scotoma sparing peripheral field. The optic disc pallor usually involves the whole neuro-retinal rim (NRR) but can be more obvious in the temporal side of the disc, often resulting in a typical sectorial atrophy known as “pie in the sky” atrophy . Approximately one third of affected patients may have subtle changes in optic disc that are passed as normal.

The diagnosis of OPA1 is based on a combination of family history, clinical findings, and visual electrophysiologic studies. Visual evoked potentials (VEPs) are typically absent or delayed; pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio. The N95 component of the PERG is specific for the retinal ganglion cell; reduction in amplitude of the N95 wave supports a ganglion cell origin for the optic atrophy. Optical coherence topography (OCT) is useful in monitoring retinal nerve fiber layer (RNFL) thickness. Molecular genetic testing is confirmatory. OPA1 is the only gene known to be associated with ADOA.

Management includes low vision aids for decreased visual acuity. Annual ophthalmic and hearing evaluation is indicated. Smoking, and excessive alcohol intake is best avoided.

KSS is a multisystem progressive disorder characterize by the triad of onset less than 20 years old, progressive external ophthalmoplegia (PEO) and pigmentary retinopathy. Affected individuals must also have a minimum of one of the following features to make the diagnosis of KSS: (1) heart block, (2) cerebellar ataxia, or (3) increased CSF protein level (>100 mg/dL) [241]. Having PEO without the other classical features of KSS is referred to as “KSS minus ” or “PEO plus ” [242]. (Di Mauro S et al. http://​www.​ncbi.​nlm.​nih.​gov/​books/​NBK1203/​. Accessed May 25, 2014). Except for the very rare cases of point mutation in tRNA genes or in nuclear genes involved in mtDNA maintenance (i.e. RRM2B), KSS typically results from single large-scale (1.3–10 kb) mtDNA deletion. Deletions of mtDNA are only exceptionally transmitted from one generation to the next and thus most cases of KSS are sporadic. The risk of a woman carrying a large size mtDNA deletion and transmitting it to her child has been estimated to be less than 4 %.

The syndrome was first reported in 1958 by Thomas Kearns and by George Sayre [243, 244]. They reported two patients with the retinitis pigmentosa, external ophthalmoplegia and complete heart block.

KSS has an estimated prevalence of 1/30,000–1/100,000. The prevalence of KSS was found to be 1.6 in 100,000 in a study of single large-scale mtDNA deletions of adults from Northern Finland [245]. In a study that involved 136 patients, Yamashita et al. found that majority of mitochondrial DNA deletions, 94/136, were associated with PEO in comparison to 33 patients who met the criteria for KSS [246].

KSS is a progressive heterogeneous syndrome with involvement primarily of the musculoskeletal, central nervous, cardiovascular, and endocrine systems depending on the tissue distribution of the mtDNA deletion. Neurological manifestations are second in prevalence to the eye features of the disease and include weakness, ataxia, cognitive decline, dysphagia, dysarthria, and seizures in addition to a high prevalence of sensorineural hearing loss [246, 247]. In the review by Khambatta et al., weakness was found in 27/35 patients (77 %), which varied from mild weakness to extreme disability, with the motor disability strongly correlated to cognitive decline [247].

Cardiac involvement includes variable degrees of heart block, cardiomyopathy, and cardiac arrest with sudden cardiac death . Sudden cardiac death and progressive cardiomyopathy are the major cause of mortality in patients with KSS [247]. Endocrine abnormalities include insulin dependent diabetes mellitus, hypothyroidism, growth hormone deficiency and adrenal insufficiency [246, 247]. Other known associations are Fanconi syndrome (reported in up to 12 %) and renal failure [246]. Typically, onset of disease usually occurs in childhood, with death commonly reported in early adulthood. (Di Mauro S et al. http://​www.​ncbi.​nlm.​nih.​gov/​books/​NBK1203/​. Accessed May 25, 2014). Patients confirmed to have KSS by muscle biopsy at more than 40 years old have been reported [248].

The eye may be the first organ to be affected in KSS. Ophthalmologic abnormalities were the most frequent presenting features (63 %) in a cohort of 35 patients with KSS which then developed in all patients during follow up years [247]. Ophthalmoplegia is the most common ocular abnormality and was seen in 86 % patients, followed by ptosis which was among the initial presenting signs (83 %) and was seen in 86 % in the follow up period. Pigmentary retinopathy was present in 17 % [247].

All extraocular muscles are commonly symmetrically involved in the two eyes. Diplopia therefore is not the usual complaint of these patients although it may present in some. The medial rectus muscles are the first to be involved and the patients may present with convergence insufficiency.

A characteristic salt and pepper retinopathy is seen in most patients. “Bone spicule” pigment clumps seen in patients with retinitis pigmentosa are not seen in KSS patients (Fig. 13.15).

Both peripheral and macula regions can be affected. Ota et al. described four stages of the ocular manifestation of KSS: Stage I: pigmentary retinopathy with normal visual function and ERG. Stage II: abnormal visual function and ERG with retinopathy, stage III: chorioretinal atrophy progresses around the optic disc and nasal retina and the ERG response is absent. Stage IV; retinopathy demonstrates the appearance of choroidal sclerosis [249]. Histopathological studies describe a local absence of rods and cones with an almost complete absence of RPE in peripheral retina. The outer retinal layer was absent in areas and most retina was gliotic [244]. Others described the presence of enlarged mitochondria in the RPE, photoreceptor inner segments and ciliary body [250]. Eagle et al. proposed that the primary defect in this type of pigmentary retinopathy resides in the RPE with secondary photoreceptor loss [251]. The ERG may show rod-cone dysfunction. Kriss and Thompson observed an increased latency of the VEP and reduced amplitude of pattern VEP in patients with KSS. In most cases, visual acuity is not affected unless the patient develops corneal exposure or maculopathy. The visual field is normal, although superior peripheral constriction may be present due to the presence of eye lid ptosis.

The diagnosis is based on the identification of the causative mtDNA deletion. The vast majority (>90 %) of these deletions are often undetectable in blood. In a series of 136 patients, eight (6 %) had mtDNA deletion that was detected in blood [246]. Hence, muscle biopsy is the gold standard for diagnosing KSS. Histology typically shows abnormal mitochondrial proliferation and RRFs on modified Gomori trichrome stain, as well as cytochrome c oxidase-deficient fibers. Southern blot analysis of muscle DNA detects the mtDNA deletion. Succinate dehydrogenase histochemical staining is even more sensitive than Gomori trichrome. [241] Grady et al. found that skeletal muscle mitochondrial DNA heteroplasmy, mitochondrial DNA deletion size and deletion location are predictive of severity and progression of a single large scale mtDNA deletion [252].

Patients with KSS require a complete ophthalmic evaluation that includes orthoptic evaluation to measure the severity of the PEO/ptosis, a slit examination of the anterior segment to look for corneal exposure and a dilated fundus examination to look for optic nerve atrophy and pigmentary retinopathy and to assess its grades. ERG , VEP and visual field testing are useful to evaluate retinal and optic nerve functions in these patients .

Treatment of KSS is supportive. Regular cardiac surveillance is recommended. Although the presence of high-grade heart block is an indication for permanent pacemaker, recent data support prophylactic pacemaker/defibrillator device even in the absence of significant ECG changes [247]. Timing of such intervention remains unclear. Hearing aids may be given to those with sensorineural deafness. Supplementation with coenzyme Q10 alone or in combination with other cofactors is a common practice. However, there is currently no clear evidence supporting the use of any intervention

Patients with ptosis may use spectacle mounted lid crutches. Ptosis surgery may be performed with extreme caution as these patients usually have poor Bell’s phenomena and overcorrection of their ptosis might result in exposure keratopathy [253]. Patients with exposure keratopathy may benefit from adhesive tapes and moisture chambers. Strabismus surgery may be offered to selected patients [254]. Indications for strabismus surgery in such patients may include severe abnormal head posture, large strabismus angle and diplopia. Surgeons should ensure the stabilization of the strabismus measurements for at least 6 months before the surgery.

Pearson syndrome is a rare multisystem disorder characterized by the presence of sideroblastic anemia and pancreatic insufficiency [255]. The syndrome is caused by oxidative phosphorylation dysfunction due to mtDNA deletion. There is high variability in the disease phenotypic expressions either between different patients or between the organs involved in same individual. This phenotypic heterogeneity is primarily related to heteroplasmy caused by random distribution of mtDNA during cell division.

Pearson in 1979 initially described the syndrome in four unrelated patients [255].

The syndrome mainly occurs in infancy. All races can be affected and there is no sex predilection. Approximately 60 cases have been described in literature, with prevalence less than 1/1,000,000.

Pearson syndrome is characterized by refractory sideroblastic anemia in childhood with vacuolization of marrow precursors and exocrine pancreatic dysfunction. Severe, transfusion-dependent, macrocytic anemia begins in early infancy and is associated with a variable degree of neutropenia and thrombocytopenia. Patients with Pearson syndrome usually die in infancy because of metabolic crisis. Death usually occurs due to severe lactic acidosis [256]. Disease survivors will have evolution of their symptoms and signs with recovery of their hematological manifestations and appearance or worsening of their neurological and myopathic abnormalities. Some develop typical KSS features with ophthalmoplegia, ptosis and pigmentary retinopathy. Pearson syndrome may be confused with Shwachman-Diamond syndrome in the presence of bone marrow dysfunction and exocrine pancreatic insufficiency. Favareto et al. summarized three main differences including the bone marrow in Pearson is normocellular compared to the leukopenic marrow seen Shwachman-Diamond syndrome, the pancreas in Pearson syndrome is fibrotic instead of the fatty infiltrated pancreas seen in Shwachman-Diamond syndrome and bony lesions are only found in Pearson syndrome [257].

Pearson syndrome survivors develop typical ophthalmic features of KSS. Kasbekar et al. reported a boy with Pearson syndrome who developed corneal endothelial dysfunction at the age of 12 years [258]. Cursiefen et al. in reported a 6 year old boy with Pearson syndrome and zonular cataract [259].

Metabolic acidosis and lactic academia is seen due to the mitochondrial respiratory enzyme defect. The diagnosis is clinched based on the presence of macrocytic anemia and ringed sideroblasts in bone marrow. Pancreatic insufficiency is diagnosed by detecting excessive fat in the stool by qualitative (Sudan stain) and quantitative (fecal fat) tests. Some patients have evidence of having deficiencies of thyroid, parathyroid, or growth hormones. The causative deletions of mtDNA can be demonstrated with molecular genetic analysis. Because of heteroplasmy, not all tissues contain abundant amounts of mutant mitochondrial DNA. Peripheral blood cells are usually the first analytic sample. If Pearson syndrome is strongly suspected with normal findings in the blood, analysis of bone marrow is performed.

No specific therapy is available for individuals with Pearson syndrome or other mitochondrial cytopathies. Awareness of possible complications and early intervention may prevent death and minimize morbidity. Red blood cell transfusions are often needed to manage the macrocytic anemia, and patients may be dependent on transfusions. Erythropoietin has been tried to decrease the frequency of transfusions. Pancreatic enzyme replacement is needed for patients with malabsorption due to exocrine pancreatic insufficiency. Supplementation with fat-soluble vitamins (ADEK) may also be needed. Although without controlled evidence of benefit, many clinicians offer supplementation with coenzyme Q and additional supplementation with carnitine and riboflavin.

Tangier disease (familial alpha-lipoprotein deficiency) is a rare autosomal recessive disorder of lipoprotein metabolism that is characterized by virtual absence of high density lipoprotein (HDL) cholesterol (less than 5 % of normal) in the plasma. HDL transports cholesterol and phospholipids from the body’s tissues to the liver, where they are removed from the blood. In Tangier disease, mutations in the ABCA1 gene (9q22-31) encoding the ATP-binding cassette transporter (ABCA1) , interfere with cholesterol and phospholipid efflux from cells to nascent HDL particles. This leads to cholesterol and phospholipid accumulation in body tissues including peripheral nerves, spleen, lymph nodes, liver, and the eye , impairing cellular functions and increasing risk of early cardiovascular disorders [327]. The presence of low plasma HDL cholesterol levels is due to a lack of cholesterol efflux and due to increased catabolism of lipid-poor HDL particles. The major clinical manifestations occur in patients with homozygous or compound heterozygous mutations in the ABCA1 gene. The biochemical phenotype is inherited as an autosomal co-dominant trait [328]. In the heterozygote, half of the normal amount of HDL is sufficient to maintain regular lipoprotein interconversion.

Tangier disease was first described by Frederickson in 1961 in two siblings with enlarged and yellowish tonsils. The disease was named after the island off the coast of the Chesapeake Bay in Virginia, USA where the patients lived.

Tangier disease is a rare disorder with approximately 100 cases reported worldwide [328].

Peripheral neuropathy, increased risk of myocardial infarction and stroke are the significant consequences of Tangier disease. Cholesterol esters accumulate in peripheral nerves causing neuropathy and in the reticulo-endothelial cells of organs such as spleen, liver, and tonsils causing their enlargement and discoloration. All affected children with Tangier disease present with classic enlarged yellow tonsils, while 50 % of affected adults present with neuropathy. Premature myocardial infarction and stroke has been reported in about 30 % of patients with Tangier disease [328]. Acute onset peripheral neuropathy has been reported as an unusual presentation of Tangier disease . Histopathological examination of the involved nerves reveals axonal degeneration, demyelination, and nerve fiber loss due to lipid infiltration [329]. Some patients with Tangier disease may have an atypical presentation with idiopathic thrombocytopenia purpura due to sequestration of platelets in enlarged spleen [330].

Diffuse hazy corneal opacification, decreased corneal sensation and lid anomalies are among the common ocular findings. Visual impairment is usually mild. Ectropion and incomplete eyelid closure may precede corneal cloudiness. Visual impairment can develop due to exposure keratopathy [331]. Histopathology studies of corneas from patients with Tangier disease have shown that corneal opacification represents lipid accumulation in the corneal stroma [332]. Confocal microscopy may be of benefit in identifying stromal lipid accumulation that may be missed in regular slit lamp examination [333].

The biochemical signs of Tangier disease are plasma HDL concentration of less than 5 mg/dl, low total plasma cholesterol (below 150 mg/dl) and normal or high plasma triglycerides. In homozygous disease there is significant reduction of HDL-cholesterol (HDL-C) and ApoA1 (both 10 mg/dL), decreased LDL cholesterol level (40 % of normal) and mild hypertriglyceridemia [334]. In heterozygous disease the HDL-C level is one half of normal individual [327]. Skin or rectal mucosa biopsy reveals foam cells in affected tissues. The diagnosis of Tangier disease can be confirmed by determining the reduced efflux of cholesterol from Tangier fibroblasts in culture medium, or by ABCA1 gene sequencing.

There is no definite treatment for Tangier disease. Tonsillectomy may be required in case of significant tonsillar enlargement. A low-fat diet helps in reducing liver enlargement and preventing atherosclerosis. New drugs such as cholesterol ester transfer protein (CETP) inhibitors (dalcetrapid and anacetrapid) and reconstituted forms of HDL may be helpful in enhancing cellular cholesterol efflux and reducing cardiovascular and neuropathic complications [328].

Patients with lid ectropion and exposure keratopathy are treated with frequent lubrication and topical antibiotics, and if indicated with lid repair procedures, to prevent subsequent visual loss.

Lecithin-cholesterol acyltransferase (LCAT) deficiency syndrome is a rare autosomal recessive metabolic disorder. LCAT plays a key role in esterification of free cholesterol, formation of high density lipoprotein (HDL) cholesterol and reverse cholesterol transport pathway, a process that describes the HDL-mediated removal of excess cholesterol from macrophages in the arterial wall and subsequent delivery to the liver for biliary excretion. There are two LCAT deficiency phenotypes: (1) familial LCAT deficiency characterized by extremely low LCAT activity and (2) Fish Eye Disease (FED) which is characterized by partial LCAT deficiency. Both these conditions are caused by mutations in the LCAT gene (16q22.1).

In 1967 Gjone and Norum described three Norwegian sisters with anemia, proteinuria, lipid deposits in the cornea, and presence of foamy cells in bone marrow and in the glomerular tuft of the kidney [335]. All three sisters had elevated plasma concentrations of free cholesterol and lecithin, reduced plasma lysolecithin, and deficiency of plasma esterified cholesterol. The enzyme LCAT could not be detected in their plasma.

The prevalence of LCAT deficiency is below 1:1,000,000. Up to 2012, approximately 70 families with partial or complete LCAT deficiency have been identified worldwide [336].

Familial LCAT deficiency is systemically characterized by hemolytic anemia, and proteinuria with renal failure. The plasma is turbid or milky in appearance. Renal involvement is a major cause of morbidity and mortality in affected patients. It starts as proteinuria in childhood and progresses to renal insufficiency by the fourth decade. Foam cells are found in the bone marrow and kidney glomeruli, and ‘sea-blue histiocytes’ are detected both in bone marrow and spleen. In FED, patients are relatively less symptomatic. They usually do not have any systemic manifestations.

Patients with familial LCAT deficiency and FED develop bilateral corneal opacification due to lipid deposition in the corneal stroma. Corneal opacification is a gradual process which usually starts early in life and often represents the initial symptom of this disease before development of anemia or renal failure, making the ophthalmologist uniquely positioned to make an early diagnosis of this disease [337, 338]. Opacification is most marked in the periphery, simulating an age-related arcus. Unlike the arcus, it tends to extend to the limbus without the sharply demarcated clear interval characteristic of arcus senilis . Although patients may complain of glare, visual acuity is usually not impaired [339]. Some patients may require penetrating keratoplasty. Histopathological evaluation with special staining techniques reveals extracellular deposits of unesterified cholesterol superimposed on the collagenous framework and Bowman’s membrane. Amyloid deposits may be detected [338]. In FED, the appearance of the eye , secondary to the dense peripheral cornea1 opacification, resembles the eyes of boiled fish; hence, the name. Cornea1 opacities are the only clinical sign of FED. They are slowly progressive and cause severe visual impairment beginning as early as 15 years.

The diagnosis of LCAT deficiency is primarily based on clinical manifestations in combination with histological findings from kidney biopsy (glomerulopathy evolving toward sclerosis with lipid deposition). Patients with LCAT deficiency have several abnormalities of their serum lipoproteins including a decrease in the levels of HDL, apo A-I and apoA-II, decrease in LDL, increase in serum levels of free cholesterol and accumulation of lipoprotein X. Patients with FED have a very low level of HDL. The HDL of plasma in FED contains only about 20 % cholesteryl esters relative to total cholesterol as compared to 75–80 % in controls. There is a normal cholesteryl ester percentage in plasma as well as a normal plasma cholesterol esterification rate as a result of the activity of β-LCAT . DNA diagnosis is also available.

Currently, there is no definite treatment for LCAT deficiency. The effect of dietary changes has been investigated. Because high fat diet may exacerbate the renal disease, patients are advised to restrict their fat consumption [340]. The effects of lipid-lowering medications and enzyme replacement therapy on improvement of this disease are being investigated.

PMM2-CDG (CDG-Ia) is the most common disorder of protein N-glycosylation and accounts for approximately 80 % of all diagnosed cases [383]. It is caused by mutations in the PMM2 gene (chromosome 16p13), that encodes phospho-mannomutase, an enzyme that transforms mannose-6-phosphate into mannose-1-phosphate. This enzyme has an essential role early in the N-glycosylation process and in the synthesis of glycosylphosphatidylinositol (GPI), which is used to anchor proteins to the cell membrane.

Clinical presentation and course of PMM2-CDG is highly variable, ranging from infants who die in the first year of life to mildly involved adults. There are three major types of clinical presentations: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. In the first stage, during infancy, systemic symptoms dominate. Patients typically present at birth with dysmorphism (long fingers and toes, inverted nipples and abnormal fat pads over the buttocks) and multiple organ affectation, with hypotonia, developmental delay, hepatopathy, coagulopathy, hypothyroidism, hypogonadism , pericardial effusions, nephrotic syndrome, renal cysts, and multiorgan failure. The disease evolves into psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy in the first or second decade [381]. Approximately 20 % of the infants die within the first year of life with infection the most common cause of death. The late-infantile and childhood ataxia-intellectual disability has an age of onset between 3 and 10 years, characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, IQ of 40–70 and stroke-like episodes. Joint contractures and skeletal deformities have been reported. In the adult form, intellectual disability is stable, peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed. Females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur.

PMM2-CDG leads to ophthalmological abnormalities in nearly 80 % of affected patients [384]. The most frequent ocular finding is strabismus which is present at birth or develops in the first year of life, and nystagmus. Other ocular manifestations include delayed visual maturation, myopia, oculomotor apraxia, congenital cataracts, congenital glaucoma and pigmentary retinopathy [384–387]. Pigmentary changes typically appear in late childhood but abnormal ERG responses may be noted as early as 2 years old. Messenger et al. reported a 14 month old infant with PMM2-CDG and nystagmus, esotropia and myopia. Her fundus showed attenuation of retinal vessels, subtle, fine, yellow dots at the macula, general hypopigmentation, and visible choroidal vessels. SD-OCT showed evidence of outer nuclear layer loss throughout the retina including the macula. ERG showed a rod- cone dysfunction with abnormal a-b wave ratios in the scotopic mixed response indicating additional photoreceptor-bipolar synaptic dysfunction. ERG abnormalities typically involving the on-pathway signifying retinal dysfunction at the cone photoreceptor synapse with the on-bipolar cell [388, 389]. A postmortem study of the retina in patients with PMM2-CDG showed degeneration and loss of photoreceptors [223]. Andréasson et al. hypothesized that the glycosylation defect involves the photoreceptor glycoprotein opsin and inter-receptor binding protein that encodes the interphotoreceptor matrix proteoglycan [385].

The other N-glycosylation defects are rarer and the ophthalmologic features are less well defined. Nystagmus, poor acuity, optic neuropathy, congenital cataracts, congenital glaucoma, and coloboma of the iris or retina have been reported. Strabismus is common in ALG6-CDG (CDG Ic) [387].

Diagnosis of protein N-glycosylation disorders relies mainly on isoelectric focusing of serum transferrin, a technique assessing the proportion and the pattern of N-glycosylated transferrin. PMM enzyme activity measurement can be performed in fibroblasts or leukocytes to rule out the most common PMM2-CDG defect. In patients with gastrointestinal involvement and bleeding diathesis, phosphomannose isomerase (MPI) should be assayed to exclude or confirm MPI-CDG. Enzymatic assays have not been developed for most CDG-related enzymes and confirmation of diagnosis is done through genetic testing. Detection of the genetic defect is essential for genetic counseling and particularly for prenatal testing, as laboratory test results for abnormal glycosylation of fetal serum protein might be false-negatives [390].

With exception of PMI-CDG (CDG Ib), no definitive treatment exists for the rest of CDG syndromes. PMI-CDG can be successfully treated with oral mannose. By producing mannose-6-phosphate, mannose intake bypasses PMI deficiency. Management of other CDGs is mainly supportive. Early intervention programs and rehabilitation is the mainstay of intervention in children and adults with neurological disease.

Aberrant O–mannosylation of α-dystroglycan, an external membrane protein expressed in brain, muscle and other tissues, causes a set of heterogeneous disorders called muscular dystrophy-dystroglycanopathies (MDDGA), characterized by severe brain and eye malformations and muscular dystrophy. The most severe disorders include Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), and Fukuyama congenital muscular dystrophy (FCMD) . They constitute a spectrum of complex brain and muscle anomalies, with subtypes numbered one to six according to the genetic cause: for example, Walker-Warburg syndrome due to POMT1 mutations is referred to as MDDGA1. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial.

Walker-Warburg Syndrome (WWS; MDDGA1) is a genetically heterogeneous disease presenting with hydrocephalus, type II lissencephaly, cerebellar malformations and eye abnormalities and congenital muscular dystrophy. Twenty percent of cases are caused by mutations in the protein O-mannosyltransferase 1 (POMT1) gene; others are caused by mutations in the fukutin (FKRP) and POMT2 genes.

The coexistence of lissencephaly and eye anomalies was first described by Walker in 1942. Later in 1971, Warburg reported several patients with retinal detachment, hydrocephalus, and lissencephaly [391]. Williams et al. described the coexistence of myopathy [392]. In Finland, Santavuori et al. described an apparently new disorder in which congenital muscular dystrophy , severe brain malformation, and abnormalities of the eyes coexisted. This autosomal recessively inherited condition was given the name muscle–eye–brain disease [393].

WWS is a rare disease with worldwide distribution. A survey in North-Eastern Italy showed an incidence of 1.2 per 100, 000 live births. MEB is more prevalent in Finland than elsewhere owing to a strong founder effect followed by genetic drift. Only a few patients have been tentatively diagnosed with MEB outside Finland [394].

Both WWS and MEB are characterized by generalized hypotonia, muscle weakness, developmental delay and, in some children, seizures . Symptoms and signs are already present at birth and early infancy, and occasionally can be detected prenatally with imaging techniques. Affected babies characteristically have cobblestone lissencephaly along with agenesis of corpus callosum and cerebellar hypoplasia, and sometimes encephalocele. This led to the earlier acronym for WWS which was HARD +/− E: hydrocephalus, agyria, retinal dysplasia with/without encephalocele (Fig. 13.18).

The CNS malformations in WWS are often more severe than in MEB. White matter changes are usually not observed after 5 years old in MEB. The facial appearance of a high prominent forehead, prominent eyes and narrow temporal regions has been described as typical for MEB. Survival of children with WWS is usually limited to less than 1 year, whereas patients with MEB often reach adulthood.

WWS and MEB have distinctive ocular findings involving both anterior and posterior segments with a wide variety of clinical presentations. The anterior segment abnormalities may include microcornea, shallow anterior chamber angle, congenital glaucoma, cataract and microphthalmia. Posterior segment involvement is characterized by high myopia, retinal nonattachment due to retinal dysplasia, optic atrophy or hypoplasia, macular hypoplasia, and optic disc and retinochoroidal coloboma [395]. Zervos et al. described the ocular findings in two siblings with MEB who were born blind with high myopia, strabismus, and retinal and optic nerve anomalies. Postmortem examination of their eyes showed retinal, choroidal and RPE atrophy and optic nerve hypoplasia [396]. The ocular manifestations of MEB are much less profound than those seen in WWS.

Laboratory investigations usually show elevated creatine kinase, myopathic or dystrophic muscle pathology and hypoglycosylation of α-dystroglycan. Although enzyme activities can be measured in leukocytes or fibroblasts, assays have not been developed for most CDG-related enzymes and confirmation of diagnosis is done through genetic testing. Antenatal molecular diagnosis is possible in families with known mutations , although antenatal ultrasound can detect hydrocephalus and retinal nonattachment early in gestation [397].

No definitive treatment exists. Management is mainly supportive and includes nutritional support, physiotherapy and medical treatment for seizures. Some patients may require surgical intervention for encephalocele or hydrocephalus. With respect to glaucoma one must assess the retinal and optic nerve prognosis for vision as well as the projected lifespan.