Basal Ganglia Disease

Patients who show early evidence of cerebral involvement should be considered for hematopoietic stem cell transplantation (HSCT).248 HSCT is not recommended for asymptomatic patients with normal MRI findings because half of them never develop the cerebral forms of X-linked ALD. Neurologically asymptomatic boys who are identified by screening at-risk relatives of known patients or those with idiopathic Addison disease have the best chance of benefitting from HSCT.224 While Lorenzo’s oil therapy does not alter the progression after the onset of cerebral disease, recent data suggest that it may significantly reduce the risk of developing cerebral disease.225

Basal Ganglia Disease

Pantothenate Kinase-Associated

Neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz syndrome,139 is a rare, autosomal recessive, childhood-onset neurodegenerative disorder associated with brain iron accumulation.92 Most patients have mutations in the pantothenate kinase 2 (PANK2) gene.342 The most common clinical features include occurrence at a young age (generally after early childhood); a motor disorder, mainly of the extrapyramidal type characterized by dystonic postures, muscular rigidity, and involuntary movements of choreoathetoid or tremulous type, but with findings suggestive of corticospinal tract dysfunction as well; mental changes indicative of dementia; and a relentless progressive course extending over several years and leading to death in early adulthood.89 A rapidly progressive earlyonset childhood type, a slowly progressive early-onset type, and a late-onset childhood type have all been described.307

Neuro-ophthalmologic abnormalities include Adie’s-like pupils, hypometric and slowed vertical saccades, and saccadic pursuit movements.92 Poor convergence and square wave jerks are also occasionally found. Peripheral pigmentary retinopathy is common, and electroretinography is often abnormal even in the absence of optic atrophy.92

The basic pathophysiology of PKAN remains unknown; however, its clinical manifestations, recessive genetic transmission, and characteristic iron deposition in the globus pallidus and substantia nigra seen on neuroimaging establish the diagnosis. The typical clinical findings include an onset in early childhood of motor disorders of an extrapyramidal type, characterized by dystonic posturing, difficulty walking, and muscular rigidity. As the disease progresses, involuntary movements of a choreoathetoid type appear along with progressive intellectual deterioration. Most patients die in early adulthood. Although optic atrophy is rare in this condition and in other degenerations of the extrapyramidal system,92 it

hasbeendescribedasthepresentingsymptominHallervorden– Spatz disease.51,353 Retinitis pigmentosa has been described in some children.89,305 Although the metabolic abnormality in Hallervorden–Spatz syndrome is unknown, it likely involves abnormal iron binding within the basal ganglia. Iron may play a role in modulating dopamine binding to postsynaptic receptors, and abnormal iron storage may interrupt these mechanisms, as well as disrupting oxidation and peroxidation reactions, leading to cellular damage within the basal ganglia.305

Iron deposition in conjunction with destruction of the globus pallidus gives rise to the characteristic “eye-of-the- tiger” sign on MR imaging.26 MR imaging may show abnormalities early in the course of this disease144, characterized by an overall low signal on T2-weighted images in the globus pallidus and substantia nigra, with a central zone of high signal within the globus pallidus26,135,253 (Fig. 10.12). The classic “eye of the tiger sign” is present once symmetrical T2 hyperintensity develops, superimposed upon the hypointense background, presumably due to gliosis.261 In some cases, the appearance of these abnormalities precedes the onset of clinical symptoms.135,144 The MR pattern of PKAN is not the characteristic of other extrapyramidal-type movement disorders, such as Parkinson disease, Wilson disease, and Leigh disease, thus allowing a fairly confident diagnosis

Fig. 10.12  Pantothene kinase-associated neurodegeneration (PKAN). Axial T2-weighted MR image shows markedly “eye-of-the-tiger sign” caused by hypointense signal in inferior globus pallidus bilaterally (arrow). Courtesy of A. James Barkovich, M.D

when this imaging pattern is seen in a child with characteristic clinical findings.

However in some cases, distinguishing PKAN from neuronal ceroid lipofuscinosis can be difficult, and it has been suggested that PKAN is a form of neuronal ceroid lipofuscinosis. Vacuoulated lymphocytes, when examined by electron microscopy, may contain abnormal cytosomes, including fingerprint, granular, and multilaminated bodies.308,361 The characteristics of the observed materials suggest the presence of ceroid lipofuscin, a substance that accumulates in neuronal ceroid lipofuscinosis. The striking rust-brown pigmentation obvious on gross examination of the globus pallidus and the zona reticulata of the substantia nigra, documented in the original descriptions, continues to be the outstanding neuropathologic characteristic of PKAN. Staining of fresh brain confirms increased iron content in pigmented areas.138,139 There is no specific treatment for this condition.

Wilson Disease

The symptoms of Wilson disease are caused by an abnormal accumulation of copper, primarily in the liver but subsequently in many other organs, including the CNS. This disease is inherited in an autosomal recessive fashion and is due to the presence of an abnormal protein in the liver that binds copper much more strongly than liver proteins in normal individuals. The copper-storing capacity is exceeded, and unbound copper increases in the circulation, with deposition in other tissues. The defect is in a copper-transporting ATPase on chromosome 13q14.3.193

Although patients are usually diagnosed in the second and third decade, they may become symptomatic as early as 5 years of age. It is estimated that 40% present with liver disease, 40% with neurologic symptoms, and 20% with psychiatric disturbances.342 Patients who are diagnosed in adolescence and in later life more often have neurological signs predominating such as loss of fine motor skills, progressive clumsiness, and dysarthria.

The principal ophthalmological sign in Wilson disease is the Kayser–Fleischer ring. Ophthalmologists are frequently asked by internal medicine and pediatrician consultants to examine patients with liver disease or unexplained neurological degeneration for Kayser–Fleischer rings, as this establishes the diagnosis of Wilson disease. A slit lamp examination is required for this evaluation although advanced Kayser–Fleischer rings can be seen by the naked eye. These rings reflect copper deposition in Descemet’s membrane, leading to a brownish-green discoloration of the membrane, seen most easily near the limbus of the cornea. Patients with Wilson disease may also have “sunflower cataracts.” Neuroophthalmologic features of Wilson disease include supranu-

clear gaze palsies, difficulty initiating saccades, cogwheel pursuit, slow vertical saccades, gaze distractibility, lid opening apraxia,178 and oculogyric crisis.182,190,193,194 In general, pursuits are more affected than saccades, and vertical movements are more affected than horizontal ones.160 Vertical smooth pursuit movements tend to be particularly affected, with vertical optokinetic responses and horizontal smooth pursuit less often affected.160

The laboratory confirmation of Wilson disease includes serum levels of ceruloplasmin (less than 20 mg/dL) and increased urinary excretion of copper (greater than 100 mg/24 h). Treatment of the condition includes a low-copper diet and D-penicillamine (a chelator of copper) in conjunction with zinc, which increases urinary excretion. Trientine can be used as a substitute for penicillamine D.

The CNS damage in Wilson disease is associated with increased tissue copper content. Copper interferes with cellular metabolism and enzymatic activity, leading to cellular death. Toxic levels of copper are found throughout the brain in this disease; however, the main pathological findings are in the basal ganglia, thalamus, and brainstem. These changes include degeneration of neurons, increased numbers of astrocytes with neurofibrillary plaques and tangles and, ultimately, spongy degeneration and cavitation of the structures.

Several studies have shown good correlation between neurological features and MR abnormalities in Wilson disease. The correlation is particularly good with moderate to advanced disease, whereas asymptomatic patients with biochemically proven Wilson disease have no MR imaging findings.5,205 Most symptomatic patients demonstrate lesions of the putamen. The characteristic lesion is a peripheral high signal area on T2-weighted imaging surrounding a central area of low signal. Pathological correlation of this finding has not been clarified. Patients with MR abnormalities limited to the putamen usually show dystonia. Patients with involvement of the putamen and caudate may show parkinsonian features as do patients with abnormal MR findings in the substantia nigra. MR imaging also shows hyperintense signal abnormalities in the lenticular nucleus, dentate nucleus, white matter, cerebellum and brainstem, along with areas of cerebral atrophy.121,160,357 However, eye movement abnormalities may be present even when no neuroimaging abnormalities are present.160

Aminoacidopathies and Other

Biochemical Defects

Maple Syrup Urine Disease

Maple syrup urine disease is caused by defects in the branched chain a-keto-acid dehydrogenase (BCKD) complex.342 The enzymatic defect is one of oxidative decarboxylation of

the ketoacids of these amino acids and can be demonstrated in leukocytes. This disease is named after the smell of urine that contains increased amounts of the three branched-chain amino acids valine, leucine, and isoleucine. It is genetically heterogenous, with gene loci found on three different chromosomes (E1aon chromosome 19q31, E1bon chromosome 6q14, and E2 on chromosome 1p31).342

This disease becomes manifest in the neonatal period with difficulties in feeding, hypoglycemia, metabolic acidosis, and a severe, progressive neurological deterioration. Supranuclear gaze palsies are frequent findings in this condition, including paralysis and paresis of upward gaze201,359 or a combination of vertical and horizontal gaze palsies.54,278 Ptosis is also frequently seen, and nystagmus commonly accompanies the recovery phase after the institution of dietary measures. This nystagmus frequently occurs in bursts, and associated bursts of flutter-like movement of the eyelids may also occur in the recovery phase.85,278,359 Untreated patients die within the first few months of life. Treatment consists of a diet limited in the branched-chain amino acids, and this can arrest the progressive deterioration of the condition. There are several variants of this condition, one of which shows responsiveness to supplementation with vitamin B1 (thiamine).234

Homocystinuria

The classical type of homocystinuria is caused by an inborn error of metabolism involving methionine metabolism. Clinical features of the untreated condition involve progressive intellectual deficiency, tall stature, arachnodactyly, malar flush, fair hair, and dislocated lenses. Affected patients are also at an increased risk of thromboembolic episodes, often involving the cerebral vasculature and sometimes brought on by anesthesia.227 Several enzymatic deficiencies may result

in a similar phenotype. Type I homocystinuria (classic) is due to the deficiency of cystathionine-b synthetase and results in high blood levels of homocystine and methionine. Neuro-ophthalmological abnormalities such as visual field defects, papilledema, and optic atrophy may arise from cerebral thromboembolic events.

Another type of homocystinuria associated with remethylation problems in the homocysteine-to-methionine cycle that uses vitamin B12 and folate as cofactors (e.g., the maculopathy and retinopathy of cobalamin C methylmalonic aciduria and homocystinuria)317 is detailed in Chap. 4. Patients with the early-onset form of this disease develop progressive retinal disease, eventually leading to atrophic macular lesions and optic atrophy with peripheral bone spicule pigmentation.121 The clinical features of this form of homocystinuria are detailed in Chap. 4.

Abetalipoproteinemia

Abetalipoproteinemia is an autosomal recessive disorder characterized by the complete absence of apolipoprotein B, causing malabsorption of all fat-soluble vitamins, including A, D, E, and K. It was first described by Bassen and Kornzweig in a patient with atypical retinitis pigmentosa, malformed erythrocytes, ataxia, and intestinal malabsorption that had led to the misdiagnosis of celiac disease.21,255 It is caused by mutations in the microsomal triglyceride transfer protein gene.354

The most prominent ophthalmological finding in abetalipoproteinemia is a pigmentary retinal degeneration (Fig. 10.13). A clinicopathologic correlation in a patient with abetalipoproteinemia dying of unrelated causes showed that the pigmentary retinal degeneration was accompanied by loss of photoreceptors in the posterior pole, loss or attenuation of pigment epithelium, excessive accumulation of lipofuscin in