Clinical Characteristics

Globoid leukodystrophy (GLD), described in 1916 by the Danish physician Knud Krabbe, has four clinical presentations, based upon age of onset. The early infantile form (3–6 months of age) presents with episodes of rigidity and opisthotonus, often in response to auditory, tactile, or visual stimuli; progressive psychomotor retardation; feeding difficulties; febrile episodes; spastic paraparesis; and optic atrophy. Results from an international registry demonstrated abnormalities in most children with early infantile form; 3-year survival is 14%. The late infantile form (6 months to 3 years) presents with ataxia, generalized hypertonicity, psychomotor regression, and visual failure. The combined incidence of these two forms is estimated at 1:100,000 to 1:200,000. The juvenile form (3–10 years of age) presents with dystonia, visual loss, and progressive spastic paraparesis, and the adult form with progressive spastic paraparesis, dementia, and optic atrophy.

Peripheral neuropathy is a prominent feature in the infantile forms, perhaps even before clinical symptoms, but is mild or absent in the juvenile and adult forms. The peripheral neuropathy is associated with elevated levels of cerebrospinal fluid protein (up to 400 mg/dL) and reduced nerve conduction velocities (NCV=10 m/s or lower). Distal latencies may be mildly prolonged. Compound motor action potential (CMAP) amplitudes may be mildly to moderately diminished. Electromyography (EMG) is normal. An infant with prenatal diagnosis demonstrated slowed NCVs at 7 weeks. Patients with the late-onset forms rarely show clinical evidence of peripheral nerve involvement, and their cerebrospinal fluid protein levels are normal or only mildly increased, but NCVs are decreased in most instances. Both axonal and demyelinating patterns have been reported in late onset Krabbe disease ; the latter occurs in about 80% of those who exhibit peripheral neuropathy (about 60% of adults).

Pathology

The main histopathological changes in the central nervous system are extensive demyelination, gliosis, and the presence of characteristic multinucleated cells, referred to as globoid cells. These phagocytic cells can be produced experimentally in rats by injecting galactosylceramide into the spleen or brain white matter. Peripheral nerves demonstrate segmental demyelination and remyelination with marked reduction in the density of myelinated fibers and a relative predominance of small thinly myelinated fibers ( Table 19.2 ). Sural nerve biopsies demonstrate Schwann cell cytoplasmic inclusions similar to those in the brain; however, classic globoid cells are not found.

Biochemistry

GLD is due to deficiency of the lysosomal enzyme galactosylceramidase (galactosylceramide-β-galactosidase), which metabolizes galactosylceramide to ceramide and galactose as well as galactosylsphingosine (psychosine) to sphingosine and galactose. Diagnosis is made by measurement of GALC activity in white blood cells, cultured skin fibroblasts, amniocytes, or chorionic villus cells. Psychosine accumulation in patients with GLD is a key factor in the pathogenesis of the disease. Animal model studies suggest an axonopathy related to psychosine.

Molecular Defect

GLD is an autosomal recessive disorder in which the gene GALC maps to 14q25-31. One hundred and forty-seven disease-causing mutations are known. The most common, a 502T/del, is present in 40% of GLD patients of European origin. The second most frequent mutation, a C>T change at nucleotide 1538, is found in approximately 10% of patients with the infantile phenotype. Mutation analysis is the most reliable method of carrier identification.

Management

Hematopoietic stem cell transplantation improves survival in babies with Krabbe disease treated within the first few weeks of life, but its benefits may be transient. Hematopoietic stem cell transplantation (HSCT) can be effective in the juvenile form of the disease but does not improve nerve conduction velocities.

Clinical Characteristics

Metachromatic leukodystrophy (MLD) presents in late infancy (most commonly), adolescence or adulthood. Onset is between 1 and 3 years of age with loss of previously acquired motor skills such as ambulation, followed later by ataxia, dysarthria and dysphagia, and impairment of cognitive function, vision, and hearing. The deficits are progressive, leading to death after several years. Occasionally, MLD presents in infancy as peripheral neuropathy without overt CNS findings ; cranial neuropathy (esotropia and facial weakness) has also been reported as a presenting feature, associated with cranial nerve enhancement on MR imaging. Neurologic examination shows evidence of both central nervous and peripheral nerve dysfunction, with hypotonia and diminished muscle stretch reflexes and positive dorsal plantar responses, ataxia, dystonic movements, and nystagmus. The juvenile form is similar to the late infantile form but with slower progression. In the adult form, behavioral and cognitive changes may precede motor changes by years or even decades. The frontal lobe syndrome in adult MLD may include disinhibition, impulsivity, poor judgment, emotional lability, social inappropriateness, and poor attention span.

Peripheral nerve involvement is a prominent feature in all forms of MLD, the combined peripheral and central nervous system involvement being an important diagnostic clue. NCVs are significantly decreased (<10 m/second) and distal latencies may be prolonged. Sural nerve biopsy shows metachromatic staining. In juvenile metachromatic leukodystrophy, diminished NCVs may prompt evaluation for combined central and peripheral nervous system demyelination. A rapidly progressive ascending paralysis has been described in an 18-month-old girl with MLD. Respiratory failure and ptosis responded to intravenous immunoglobulin, but limb weakness did not, suggesting that the child had an immune-mediated neuropathy superimposed on the chronic neuropathy of MLD.

Pathology

The pathology of MLD consists primarily of demyelination and metachromatic granule deposition in the central and peripheral nervous system ( Figure 19.1 ). These changes can also be seen in the kidney, urine (urinary sulfatide excretion is increased), and other tissues. Viewed by electron microscopy the metachromatic granules present a hexagonal honeycomb pattern, and are referred to as tuffstone bodies. Peripheral nerves show segmental demyelination, with metachromatic granules singly or in clusters in Schwann cells ( Table 19.2 , Figure 19.2 ), in endoneurial macrophages, and to a lesser extent in the Remak cells associated with unmyelinated nerve fibers. In addition to the expected metachromatic granules revealed by cresyl violet staining, one study of 40 cases of nerve biopsies in MLD showed accumulation of orthochromatic granules in perivascular macrophages, suggesting storage of multiple species of glycosphingolipids.

( A ) Metachromatic leukodystrophy: Cross-section of sural nerve demonstrating metachromatic material (arrows) and irregular myelin sheaths. Methylene blue. ×400. ( B ) Metachromatic leukodystrophy: Longitudinal section of sural nerve demonstrating metachromatic material within Schwann cell cytoplasm (black arrows) and narrowing of myelin sheath (white arrow). Cresyl violet. ×400.

( A ) Metachromatic leukodystrophy: Electron micrograph of sural nerve in cross-section, demonstrating excess interstitial collagen (black arrow) and remyelination (white arrow). ( B ) Metachromatic leukodystrophy: Electron micrograph of sural nerve in longitudinal section demonstrating granular inclusions in Schwann cell cytoplasm (small white arrows) and excess interstitial collagen (large white arrow). ×12,000.

Biochemistry

The key abnormality in MLD is the accumulation of sulfatide (galactosylceramide-3-sulfate), the metachromasia due to the sulfate group. Deficiency of the lysosomal enzyme arylsulfatase-A (ASA), which cleaves sulfatide to galactosylceramide and sulfate, is the most common cause of sulfatide accumulation, with an estimated incidence of 1:40,000. Diagnosis of ASA deficiency can be determined in white blood cells, cultured skin fibroblasts, amniocytes, or chorion villus cells. Great caution must be used to distinguish MLD from a condition referred to as pseudoarylsulfatase deficiency (PSD). PSD is a common and entirely benign condition in which ASA activity is reduced, at times to levels nearly as low as in MLD. Persons with PSD do not display any of the clinical manifestations of MLD. Distinction between PSD and MLD is crucial in prenatal studies and in asymptomatic infants or adults. Molecular analysis and measurement of urinary sulfatide levels aid the distinction. Urinary sulfatide levels are increased in MLD but not PSD. Less commonly, sulfatide accumulation is due to multiple sulfatase deficiency, in which at least seven sulfated lipids or mucopolysaccharides accumulate. The third and least common cause is a deficiency of saposin B, one of the sphingolipid activator proteins, which is required for the biological activity of ASA. Mutations in the PSAP gene, which encodes saposin B, are associated with a wide variety of phenotypes.

Molecular Defect

All forms of MLD are transmitted as autosomal recessive traits, the gene, ASA , mapping to 22q13, with more than 150 mutations identified. Mutations that abolish function completely cause the severe late infantile phenotype. Missense mutations, in which up to 3% to 5% of normal activity is maintained, tend to be associated with the adult form of the disease. Individuals who are heterozygous for a null mutation and one of the milder missense mutations often have the juvenile phenotype of MLD.

Management

Bone marrow transplantation (BMT) can stabilize or slow the rate of progression of central nervous system dysfunction, and stabilize peripheral nerve involvement in patients with the juvenile, but not the early infantile presentation of MLD. BMT is recommended only for patients with relatively mild nervous system involvement, or for asymptomatic patients identified by testing of at-risk relatives, with care taken to differentiate MLD from PSD. The procedure is not recommended for patients with advanced involvement, as it is associated with a high risk of additional worsening of the disability. Gene therapy is under investigation in cultured cells and in animal models. Enzyme replacement therapy is currently in human trials, after promising results in animal models.

Cholecystectomy is occasionally required in those in whom the accumulated sulfatide has formed gallstones.

Clinical Characteristics

Trihexosylceramide lipidosis (angiokeratoma corporis diffusum universale, Fabry disease) was described independently in 1893 by Fabry and Anderson. Among the sphingolipid storage diseases, it is the only X-linked disorder. The principal clinical manifestations involve skin, heart, kidney, and peripheral nerve.

The hallmark of Fabry disease is its cutaneous manifestation— angiokeratoma —violaceous angiectatic lesions over the genitalia, thighs, buttock, back, and lower abdomen. Similar lesions may be seen in the oral mucosa. Angiokeratomata have also been described in fucosidosis, β-mannosidosis, galactosialidosis, and Schindler disease, and are not specific for Fabry disease. Fabry disease has its onset most commonly in adolescence or early adulthood. Despite significant chronic medical issues, survival is often quite prolonged. Ultimately, renal or cardiac involvement will determine longevity. Cardiac manifestations include left ventricular hypertrophy, valvular dysfunction (especially mitral insufficiency), and conduction abnormalities. Death usually occurs in the fourth or fifth decades.

Chronic renal disease poses the major clinical problem. As such, Fabry disease had been regarded as the best candidate among the sphingolipidoses for direct therapeutic intervention. However, improvement of renal function with dialysis or renal transplantation has not reversed other aspects of the disease.

The most common neurological problem is a painful peripheral neuropathy, which generally involves the distal extremities (acroparesthesias). Clinical features include both severe crises of lancinating pain and chronic, unremitting pain. The painful crises may be precipitated by exercise, fatigue, stress, or exposure to sunshine or hot weather. Decreased sweating (hypohidrosis) leads to temperature intolerance and untoward responses to sun exposure.

Other common features are corneal and lenticular opacifications and retinal vasculopathies. CNS vaso-occlusive events may be noted, and Fabry disease should be considered in the differential diagnosis of stroke in the young individual. Cranial imaging often demonstrates changes consistent with stroke, even the absence of a history of stroke-like events. Occasionally, lymphedema and episodic diarrhea may be significant problems. Both are attributed to lipid storage.

Female carriers (heterozygotes) of trihexosylceramide lipidosis may develop signs similar to those in affected males, although typically much later in adulthood. Corneal opacifications are the most common signs, being present in nearly three-fourths of carriers. Other features are less prevalent but equally severe to those seen in men.

Pathology

Lipid materials accumulate in vascular smooth muscle and endothelium, kidney, cornea, peripheral nerves, and in neurons of the autonomic nervous system, both central and peripheral. Electron microscopy of peripheral nerves reveals lamellar inclusions in perineurial cells. Similar lamellar inclusions can be demonstrated in vascular smooth muscle. The degree of peripheral nerve involvement can be easily assessed by analysis of biopsy specimens ( Table 19.2 ). A decrease in small peripheral sensory neurons may be noted.

Biochemistry

Deficient α-galactosidase (trihexosylceramide α-galactosidase) activity is the basis for Fabry disease. Trihexosylceramide is an important membrane sphingolipid in kidney and the first intermediate in the degradation of globoside, the prominent sphingolipid of red cell membranes. In Fabry disease, trihexosylceramide accumulates in kidney, liver, and lung from 30 to 300 times normal levels. A lesser degree of digalactosylceramide accumulation is also seen, primarily in the kidney. Diagnosis can be made in leukocytes and cultured skin fibroblasts, and numerous mutations are described.

Management

The painful and disabling dysesthesias of hands and feet may be treated with carbamazepine, phenytoin, gabapentin, or pregabalin. The systemic clinical manifestations, including neurological problems, arise from vaso-occlusion due to sphingolipid deposition in vascular endothelial cells, and may be difficult to treat. Renal transplantation may be required for end-stage kidney disease, but does not usually result in overall clinical and biochemical improvement.

Enzyme replacement therapy (ERT) was approved for use in Fabry disease in Europe in 2001 and in the USA in 2003; the response to therapy is variable. ERT appears to be least effective in individuals with advanced disease. ERT reduces neuropathic pain, improves the detection threshold for cold and warm sensation in the hand and foot, and leads to improvement in sweating and heat tolerance, but not does not fully reverse peripheral nerve involvement in Fabry disease. The extent of renal impairment correlates with small fiber response to ERT; i.e. patients with more severe renal impairment have a more severe neuropathy. The deacylated product, trihexosylsphingosine, has been suggested as a useful biomarker following ERT for Fabry disease. Newborn screening in Fabry disease suggests a high frequency of under-diagnosis of later onset forms that could be treated effectively if diagnosed.

Clinical Characteristics

Peripheral nerve involvement in α-N-acetylgalactosaminidase deficiency (Schindler disease) is much more marked than in the other glycoproteinoses. The hallmark of Schindler disease is a central and peripheral axonopathy.

Schindler disease is a very rare disorder, described in only a small number of individuals. An acute form has its onset from 9 to 15 months as an exaggerated startle response after normal early infancy. Psychomotor deterioration is rapid, leading to marked spasticity, cortical blindness, and myoclonic epilepsy. The EEG shows background slowing and multifocal spike and spike and wave activity. The VER, ABR, and SSEP are reduced, whereas NCV and ERG are normal.

A chronic form features mild cognitive impairment and slow progression with dilated, tortuous retinal vessels and cutaneous angiokeratoma, most prominent over the torso.

Pathology

An axonal neuropathy is prominent, resembling that of infantile neuroaxonal dystrophy. Axonal spheroids are present in peripheral nerve axons and in axons ranging from cerebral cortex to the myenteric plexus. Electron microscopy revealed membranous cytoplasmic bodies in these tissues. α-N-acetylgalactosaminidase B deficiency, which establishes the diagnosis, may be measured in leucocytes or cultured skin fibroblasts. This enzyme is identical to its isomer, α-galactosidase A, the deficient enzyme in Fabry disease.

The only three patients described with Schindler disease and neuroaxonal dystrophy were all related; this observation, and the wide range of phenotypes associated with α-N-acetylgalactosaminidase B deficiency, has led some authors to propose that children with enzyme deficiency and the neurological phenotype also have mutations in the calcium-independent phospholipase A ₂ gene, PLA2G6 , which is the cause of infantile neuroaxonal dystrophy.

Pathology

Pathologically, lipid storage is evident in the leptomeninges, the ependyma, the choroid epithelium, the liver, and the kidneys. The peripheral nerves are enlarged by a hypertrophic neuropathy with onion bulbs and segmental demyelination. Electron microscopy shows the frequent presence of lipid granules in the Schwann cell cytoplasm. The central nervous system may show diffuse myelin destruction around the inferior olivary nuclei and in the brain stem and dentate nucleus. The retina shows an almost complete loss of photoreceptors, thinning of the inner nuclear layer, and reduction in the number of ganglion cells.

Biochemistry

The principal biochemical abnormality is the accumulation of phytanic acid, a branched chain fatty acid, 3,7,11,15-tetramethylhexadecanoic acid, which is toxic to cells and is exclusively of dietary origin.

Phytanic acid levels are increased in the plasma. Due to the presence of the α-methyl group, phytanic acid cannot be degraded by the beta-oxidation mechanism used for most fatty acids, and an alpha oxidation reaction that results in the oxidation of phytanic acid to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) is the first step in phytanic acid degradation.

The enzymatic defect in Refsum disease, phytanoyl-CoA hydroxylase deficiency, has been localized to the peroxisome. Phytanic acid accumulates in several peroxisomal disorders other than Refsum disease, including rhizomelic chondrodysplasia punctata and deficiency of peroxisomal bifunctional enzyme and the disorders of peroxisome biogenesis, infantile Refsum disease, neonatal adrenoleukodystrophy, and Zellweger syndrome. Determination of the ratio of phytanic to pristanic acid and the measurement of other peroxisomal functions aid the distinction between Refsum disease and these other disorders. In Refsum disease, biochemical defects are usually confined to phytanic acid, except for what appears to be an allelic disorder in which pipecolic acid levels are also increased. Plasma phytanic acid levels are elevated, while the levels of pristanic acid, which is below the metabolic block, are low or undetectable.

Molecular Defect

Refsum disease is inherited as an autosomal recessive trait, the gene encoding phytanoyl-CoA hydroxylase, PHYH , mapping to 10p. A subgroup of affected individuals (about 10% of patients with clinical and biochemical features of Refsum disease), do not have mutations in PHYH , but rather in PEX7 , which encodes the peroxin 7 receptor protein, an important component of the peroxisomal protein import system. A disorder with features mimicking Refsum disease, but with normal phytanic and pristanic acid levels, has been reported in a consanguineous Norwegian kindred and linked to chromosome 20.

Management

Dietary therapy is based on the knowledge that phytanic acid, which is derived exclusively from dietary intake, is the toxic agent in this disease. Reduction of dietary phytanic acid intake lowers plasma levels of phytanic acid over some months. This goal can be accomplished by restricting the intake of products from ruminant animals and fish. The contribution of phytanic acid from vegetables is negligible. Brown et al. have measured the phytanic acid content of 151 foods and provide practical guidelines on how to provide a nutritionally adequate and acceptable diet. Dietary therapy improves peripheral nerve function and appears to stabilize central nervous system deficits. Early, presymptomatic diagnosis combined with prompt institution of dietary therapy may prevent many disease sequelae. Very high plasma levels of phytanic acid may produce toxic and life-threatening symptoms, including quadriparesis and cardiac dysfunction, necessitating the use of plasmapheresis.