While there is no known treatment for LHON, experimental rescue of LHON cells with the 11778 mutation using adeno-associated viral vector containing the human mitochondrial superoxide dismutase (SOD2) gene offers promise that gene therapy may soon play a role in the treatment of LHON and other mitochondrial disease.326,697

Recessive Optic Atrophy

Recessively inherited optic atrophies are a heterogeneous group of disorders. One end of the spectrum is represented by complex and overlapping conditions such as Behr’s optic atrophy and Costeff syndrome, as well as various recessively inherited neurologic disorders that show optic atrophy as one of their manifestations. The other end of the spectrum is represented by a monosymptomatic, isolated, rare form of hereditary optic atrophy that occurs as an autosomal recessive disorder.

Simple recessive optic atrophy is present at birth or develops at an early age.268,457,911 The visual deficit in this rare disorder is more pronounced than in dominant optic atrophy, with acuities worse than 2/200 and achromatopsia or severe dyschromatopsia being characteristic. The condition is therefore detected earlier in life than dominant atrophy, usually within the first several years of life, and is usually associated with nystagmus. Occasionally, the condition is noted in the neonatal period and labeled as congenital. Visual fields show variable constriction, often with paracentral scotomas. Because of the rarity of the condition, other, more common, disorders must first be excluded by thorough clinical, electrophysiological, and neuroimaging means.172

The optic discs show profound diffuse atrophy, often with deep cupping. Attenuation of the peripapillary retinal arteriolar vessels has been described, suggesting that at least some such cases might have represented undiagnosed retinal dystrophies such as Leber congenital amaurosis or autosomal recessive cone dystrophy with associated optic atrophy that went unrecognized in the pre-ERG era.267 Therefore, a complete retinal evaluation and a normal ERG are essential to make a diagnosis of autosomal recessive optic atrophy. In an infant with Leber congenital amaurosis, however, optic atrophy is distinctly unusual,745 and a compressive intracranial etiology should be sought. Also, histopathologic studies of eyes with Leber congenital amaurosis have revealed intact optic nerves, the outer nuclear layer and photoreceptors being the primary site of retinal pathology.744

Although some authors have cast doubt on the existence of simple, monosymptomatic, recessively inherited optic atrophy as a distinct entity,583 the locus for autosomal recessive isolated optic atrophy was recently mapped to the long

arm of chromosome 8 in a French family.48 Given the rarity of this disorder, the diagnosis should be one of exclusion that carries with it the need for specific genetic counseling to prospective parents.

X-Linked Optic Atrophy

Several pedigrees with isolated X-linked optic atrophy have been documented.

Assink et al34 analyzed four males from a Dutch pedigree with X-linked optic atrophy who had visual acuities between 20/80 and 20/1,000, with severe optic atrophy and severe color vision defects that differed from dominant optic atrophy by the absence of tritanopia. Katz et al430 found similar linkage in 15 members of an extended pedigree. Affected individuals have visual acuities ranging from 20/30 to 20/100 with significant optic atrophy, absence of nystagmus in most patients, and no other neurologic abnormalities. Obligate female carriers had normal acuity, color vision, perimetry, and normal disc appearances. The gene product for OPA2 has not yet been determined.363

Older reports of X-linked optic atrophy probably included a diversegroupofpatients,someofwhomhadCharcot–Marie–Tooth disease, with others having Rosenberg–Chutorian syndrome.430

Behr Syndrome

In 1909, Behr59 described a variant of recessive optic atrophy that also occurs in early childhood (1–8 years). It differs from the simple variety previously described in that it is associated with other abnormalities, including ataxia, pyramidal and extrapyramidal dysfunction, hypertonia, juvenile spastic paresis, mental retardation, urinary incontinence, and pes cavus. Muscle contractures, mainly of the hip adductors, hamstrings, and soleus, are progressive and become more prominent in the second decade.170 Although usually autosomal recessive, pseudodominant and autosomal dominant inheritance do occur. The visual disability and optic atrophy are severe, showing a variable period of progression that does not usually extend beyond childhood. Sensory nystagmus occurs in over half of the patients. MR neuroimaging in a 6-year-old girl with this syndrome demonstrated diffuse, symmetric white matter abnormalities, including the optic radiations, internal capsule, and centrum semiovale.543

It is doubtful that Behr optic atrophy is a distinct entity, with recent evidence suggesting that the syndrome may represent a number of nosologically and genetically separate disorders. Some cases may represent undiagnosed

adrenoleukodystrophy or hereditary ataxia during the era when diagnostic testing for these entities was not available. Other cases may represent undiagnosed cases of 3-methyl- glutaconic aciduria,175,794 a syndrome with similar clinical features to Behr syndrome. Sheffer794 examined three patients who fulfilled the diagnostic criteria of Behr syndrome and who excreted excessive amounts of 3-methylglutaconic acid and 3-methylglutaric acid in their urine. This autosomal recessive disorder, also known as methylglutconic aciduria type III or Costeff syndrome, is characterized by early bilateral optic atrophy, later-onset spasticity, extrapyramidal dysfunction, ataxia, and occasional cognitive defects.174,175,236,363 Patients with Costeff syndrome tend to have extrapyramidal dysfunction without ataxia, whereas those with Behr syndrome tend to have ataxia without extrapyramidal dysfunction, although some overlap exists.175 It is caused by a homozygous mutation in the optic atrophy 3 gene (OPA3), which encodes a protein that is localized to the mitochondrial inner membrane.363 Homozygous mutations with complete absence of the OPA3 gene produce Costeff syndrome, whereas missense mutations in one copy of the OPA3 gene produce autosomal dominant optic atrophy with cataract.363

Straussberg et al829 reported seven Iraqi Jewish children with 3-methyl glutaconic aciduria who were initially misdiagnosed as having cerebral palsy and cautioned that this diagnosis should be considered in the differential diagnosis of cerebral palsy, especially when neurologic symptoms are slowly progressive. Because the two disorders may be clinically indistinguishable, testing for elevated urinary excretion of 3-methylglutaconic acid should be included in the diagnostic evaluation of Behr syndrome.

The diagnosis of Behr syndrome should be considered in patients with heredofamilial ataxia and optic atrophy.253 Its differential diagnosis includes NARP (nyctalopia, ataxia, retinitis pigmentosa) syndrome,292 Marinesco–Sjogren syndrome (a rare autosomal recessive disorder featuring cataracts, cerebellar ataxia, and mental retardation)288 and other spinocerebellar degenerations,181 and other rare congenital cerebellar ataxias such as CAMOS (cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities) syndrome,196 CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome,624 and Nyssen–Van Boegaert syndrome.484 Because there are no hallmarks, the diagnosis of Behr’s syndrome is based on exclusion criteria.253

Wolfram Syndrome (DIDMOAD)

Originally described as an association of diabetes mellitus and optic atrophy by Wolfram,937 the spectrum of this syndrome was subsequently expanded to include central diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural

Table 4.3  Neurologic manifestations of Wolfram (DIDMOAD) syndrome

Diabetes insipidus Optic atrophy Nystagmus Ptosis

Lacrimal hyposecretion

Pupillary abnormalities (e.g., internal ophthalmoplegia) Sensorineural deafness

Seizures

Anosmia Psychiatric disorders Low IQ

Ataxia

Hypogonadotrophic hypogonadism Neurogenic bladder

deafness (hence, the acronym DIDMOAD).22,680,747,757,893 Other, less common, phenotypic features include ptosis, brachydactyly, anosmia, ataxia, nystagmus, seizures, mental retardation, psychiatric disorders, abnormal ERG, elevated protein and cell count in the spinal fluid, small stature, congenital heart disease, myocarditis, and genitourinary abnormalities (Table 4.3).497,708 The typical urinary tract abnormalities include muscular atony with bilateral hydronephrosis and hydro­ ureters. The mode of inheritance is generally considered autosomal recessive or sporadic, but recently, some cases of Wolfram syndrome have been proposed to represent a mito- chondrial-mediated disorder. It has been suggested that the constellation of findings in Wolfram syndrome fulfill the criteria for a genetic defect of the mitochondrial energy supply.108 These criteria include the following (1) an unexplained association of symptoms and signs, (2) with an early onset and a rapidly progressive course, and (3) which involves seemingly unrelated organs that share no common embryological origin or biological function.598 Alternatively, a combination of mitochondrial and nuclear genetic defects have been postulated to explain the pleiotropic features of DIDMOAD syndrome.108 Some have proposed that the DIDMOAD syndrome results from an inherited abnormality of thiamine metabolism.83

The optic atrophy initially shows rapid progression then plateaus before complete blindness occurs in most cases. Vision is usually reduced to less than 20/200. Pigmentary retinopathy and abnormal ERGs have been described in some cases, indicating the possibility of a more widespread retinal abnormality.

The ages of most patients described in the literature are under 25 years, with many under 15 years. The onsets of the various manifestations of the syndrome are usually temporally separated from each other by months to years. The mean age at diagnosis of diabetes mellitus is 9 years, optic atrophy at 12 years, and diabetes insipidus at 15–20 years. Hearing loss may be detectable only by audiography before the age of 20 years. The fact that diabetes mellitus occurs first in most patients led to the earlier impression that many

of the features of the syndrome represent diabetic microvascular complications. This now seems unlikely.453 Optic atrophy and other neurologic abnormalities may appear before diabetes mellitus and usually develop in the absence of any complications related to hyperglycemia.321 The syndrome may remain unrecognized in many patients because the symptoms, except diabetes mellitus and optic atrophy, occur with varying expressivity.159,217 The occurrence of optic atrophy and diabetes mellitus without other manifestations of the syndrome makes the diagnosis difficult to establish, especially in sporadic cases.

The DIDMOAD syndrome should be suspected in diabetic children with unexplained visual loss or persistent polyurea and polydipsia (due to unsuspected diabetes insipidus) in the presence of adequate blood sugar control. The associated hearing loss may be subtle, often a mild highfrequency loss, and must be investigated. Atonia of the efferent urinary tract, which is said to occur in half of patients, is associated with recurrent urinary tract infections and even fatal complications.52 Other systemic and neurologic abnormalities may include regression of milestones, seizures, myoclonus, choreiform movements, ataxia, abnormal behavior, and a bleeding diathesis (Table 4.3).23,137,555 Median age at death is 30 years, most commonly attributable to central respiratory failure with brainstem atrophy.137

MR imaging is highly abnormal, with widespread atrophic changes involving the brainstem, middle cerebellar peduncle, and cerebellum, along with the absence of the high-intensity signal of the posterior pituitary that is consistent with degeneration of the supraoptic and paraventricular nuclei of the hypothalamus.398,660,708,778 In one 12-year-old girl, however, T2-weighted and proton density images showed high signal in the right substantia nigra with no evidence of atrophy.275

Differentiation from simple recessive optic atrophy is made on the basis of the congenital onset and the isolated nature of simple recessive optic atrophy. DIDMOAD is readily distinguished from complicated forms of recessive optic atrophy (such as Behr or Costeff syndrome) on the basis of the serious CNS dysfunction (mental retardation, spasticity, hypertonia, ataxia) and the early age of onset of Behr syndrome. The disorder should be readily differentiated from other disorders showing a combination of diabetes mellitus and optic atrophy, namely Friedreich ataxia, infantile Refsum disease, Alstrom syndrome, and Bardet–Biedl syndrome. The DIDMOAD syndrome can be distinguished from other syndromes showing a combination of optic atrophy and hearing loss, such as Sylvestor syndrome,840 Jensen syndrome,407 or a recently described syndrome showing a triad of optic atrophy, hearing loss, and peripheral neuropathy334 on the basis of other clinical characteristics, the time course of emergence of the various stigmata, and the modes of transmission.

Mutations in the WFS1 gene at 4p16.3 are associated with either optic atrophy as part of the autosomal recessive

Wolfram syndrome, with dominant optic atrophy with hearing loss, or with autosomal dominant progressive low-frequency sensorineural hearing loss without any ophthalmological abnormalities.213,229,739 In several families with presumed autosomal dominant inheritance, Wolfram gene was localized to the short arm of chromosome 4 (4p16.1).684 However, this locus does not account for all Wolfram pedigrees. The gene at this locus has been designated WFS1, and multiple point mutations and deletions have been identified.354,891 Some of these mutations have been found to be a common cause of inherited isolated low-frequency hearing loss. In one report,53 the locus on chromosome 4p16 was proposed as a predisposing factor for the formation of multiple mitochondrial deletions. DIDMOAD patients were also found to exhibit a preponderance of two major mtDNA haplotypes that are also overrepresented among LHON patients.364 That many associated abnormalities in Wolfram syndrome are commonly encountered in patients with mitochondrial disease has led to speculation that the Wolfram phenotype may be nonspecific and reflect a wide array of underlying genetic defects in either the nuclear or mitochondrial genomes, with a unifying pathogenesis in mitochondrial dysfunction.618

Toxic/Nutritional Optic Neuropathy

Symmetrical, usually insidious bilateral optic neuropathy may result from nutritional deficiency (e.g., thiamine, vitamin B12, pyridoxine, folic acid, cobalamin, riboflavin). Children with a history of malnutrition, on starvation diets (e.g., teenagers with anorexia) or other unusually restrictive diets, or gastrointestinal malabsorption disorders should be particularly suspected of harboring this diagnosis (Fig. 4.13). The diagnosis of vitamin B12 deficiency should be considered in the child with “sporadic” dominant optic atrophy (R. Michael Siatkowski, verbal communication). Hoyt and Billson372 described two children who developed symmetrical, bilateral optic neuropathy while being treated with ketogenic diets for seizure control. Both patients recovered normal visual acuity following treatment with thiamine. The epidemic optic neuropathy afflicting Tanzanian schoolchildren in their second decade of life may be partly attributable to low serum levels of B group vitamins.91a

Optic atrophy may arise from adverse metabolic effects of certain drugs (e.g., ethambutol, chloramphenicol, rifampin, Carmistine [BCNU], vincristine) and toxins (e.g., methanol, lead, cobalt). Numerous substances have been implicated in causing optic atrophy.313,355 Chloramphenicol can produce an optic neuropathy that is akin to Leber Hereditary optic neuropathy.789 Before its discontinuation, some patients with cystic fibrosis treated with chloramphenicol presented with sudden bilateral loss of vision, central scotomas, papilledema, engorgement of the retinal veins, and subsequent disc pallor.355 It was subsequently discovered that chloramphenicol acts as