Irina A. Anselm
Lysosomal storage disorders (LSDs) comprise a group of approximately 30 relatively rare inherited diseases that are characterized by defective functioning of one or several lysosomal enzymes. As a result of the enzyme deficiency, a storage material (glycogen, glycoproteins, shingolipids, cholesterol) accumulates in various organs, including central nervous system (CNS), liver, spleen, and kidneys. While most individual LSDs are quite rare, as a group their incidence is estimated to be between 1:5000 to 1:10,000. The prevalence of some of LSDs is higher in certain populations. LSDs are classified based on the type of the enzymatic defect or type of stored substrate product. Clinical symptoms (both somatic and neurological manifestations) tend to progress as the substrate accumulates over time. Several LSDs with CNS involvement are discussed below. These disorders are further discussed in Chapters 160 and 161. Diagnosis is usually made by enzyme assay or mutation analysis. Hematopoietic stem cell transplant (HSCT) has been used for the treatment of several LSDs over the past three decades. Enzyme replacement therapy (ERT) became available for the treatment of few LSDs in the past 15 years. New therapies have emerged in most recent years; small molecule drugs (chaperones) can reduce substrate production (substrate reduction therapy) or increase residual enzyme activity (enzyme enhancing therapy). Gene therapy may become available for the treatment of some LSDs in the future and is under investigation.
LYSOSOMAL DISORDERS PRIMARILY AFFECTING GRAY MATTER
LYSOSOMAL STORAGE DISEASES CONTAINING LIPID
GM1 GANGLIOSIDOSIS
GM1 gangliosidosis is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme, GM1 ganglioside β-galactosidase, a lysosomal enzyme requiring a complex of sphingolipid activator protein (saposin B), protective protein, and neuraminidase enzyme in order to function properly. β-galactosidase deficiency results in accumulation of GM1 ganglioside within the brain and storage of galactose-containing glycoproteins and keratan sulfate within various body organs.
Deficiency of β-galactosidase is expressed clinically as 2 different diseases: GM1 gangliosidosis and Morquio B disease. GM1 gangliosidosis is characterized by a neurodegenerative process with associated visceral involvement. Generalized bone disease without CNS involvement is the hallmark of Morquio B disease. Molecular analysis has confirmed allelic mutations of the same gene in these diseases mapped to chromosome 3 (3p21.33).
The clinical phenotype of GM1 gangliosidosis can be divided into 3 forms: type I (infantile), type II (juvenile), and type III (adult). Type I, or infantile, form presents at birth or during early infancy with characteristic facial appearance of depressed nasal bridge, frontal bossing, epicanthal folds, puffy eyelids, gingival hypertrophy, enlarged tongue, low-set ears, and small jaw. Peripheral and facial edema may be seen. Other features include skeletal dysplasia, manifesting as thoracolumbar kyphoscoliosis and hepatosplenomegaly. Vision is poor; a cherry-red macula develops after several months in at least 50% of children. MRI may show progressive atrophy and delayed myelination. Peripheral blood smear analysis frequently shows vacuolated lymphocytes. Patients become vegetative and die within a few years after onset. Type II, or juvenile-onset, disease has onset usually between 1 and 2 years; symptoms consist of mild bony changes without dysmorphic features. The disease primarily affects the CNS and manifests as gradual developmental delay, ataxia, and chore-oathetoid movements. The first symptom is usually difficulty with walking, followed by loss of speech. A retinal cherry-red spot is usually not present. There is no hepatosplenomegaly. MRI is usually normal, and EEG may be diffusely slow but not diagnostic. The course is protracted, with death usually occurring within the first decade. Type III adult-onset disease is characterized by late-onset neurologic symptoms.
Morquio disease type B is also associated with deficiency of β-galactosidase. Patients present with generalized skeletal dysplasia without CNS involvement. Despite the enzymatic defect, the phenotype resembles systemic manifestations of other mucopolysaccharidoses.
Galactosialidosis is a complicated variant of GM1 gangliosidosis involving deficiency not only of GM1 ganglioside β-galactosidase, but also of neuraminidase. The biochemical defect is caused by a deficiency of the protective protein, cathepsin A. The gene for cathepsin A is located on chromosome 20, and several mutations have been identified in this disease. Clinical presentation is frequently a severe infantile onset with dysmorphic and neurologic features similar to infantile GM1 gangliosidosis. Many milder variants have been described, making the phenotype quite heterogeneous.
GM2 GANGLIOSIDOSES
The GM2 gangliosidoses are a collection of lysosomal diseases associated with the accumulation of GM2 ganglioside in the lysosomes, predominantly of nervous system cells. The diseases may be caused by a deficiency of β-hexosaminidase A, β-hexosaminidase A and B, or GM2 ganglioside activator protein. Two isoenzymes of β-hexosaminidase exist: Hex A (structure αβ) and Hex B (structure ββ). Tay-Sachs variant is caused by defects in the α-subunit of the enzyme and is associated with deficiency of Hex A and normal activity of Hex B. Sandhoff disease is caused by mutations in the β-subunit gene that result in deficiency of both Hex A and B. The genes encoding the β-hexosaminidase α-subunit (HEXA gene) and β-subunit (HEXB gene) are similar in structure, with nearly 60% nucleotide and amino acid homology, but have been mapped on 2 separate chromosomes, with HEXA localized to 15q23-24 and HEXB to 5q11.2-13.3. The GM2 ganglioside activator protein was mapped to chromosome 5. All 3 genes have been cloned and mutations identified.
Tay-Sachs Disease (β-Hexosaminidase α-Subunit Deficiency)
The infantile onset of β-hexosaminidase α-subunit deficiency (Tay-Sachs disease) begins within the first few months of life. The first symptom is an excessive startle in response to noise, tactile stimuli, or light flashes. This startle response differs from the Moro response of normal infants and consists of quick extension of the arm and legs, frequently with clonic movements, and does not attenuate with stimulus repetition. As the disease progresses, motor development slows and previously acquired skills are frequently lost, along with decreased vocalizations and loss of awareness of the environment. A macular cherry-red spot (Fig. 574-1) occurs in over 90% of infants. Storage of lipids within the retinal ganglion cells causes whitish discoloration of most of the retina except for the fovea, which shows the normal red color. Macrocephaly becomes apparent by the second year. Affected children may develop seizures that can be induced by auditory stimuli. Systemic organs are spared in this form of the disease. A vegetative state develops between age 2 and 3 years and is followed by death in a few years, usually from infection. A late-onset (juvenile/adult) variant of GM2 gangliosidosis, with indolent clinical presentation, has been described. Diagnosis of Tay-Sachs disease (TSD) relies upon the demonstration of absent or extremely low activity of Hex A in white blood cells or other tissues. Before community-based carrier-screening programs were developed in the Ashkenazi Jewish population, the incidence of TSD was about 1 per 3600 births of infants of this descent. The carrier rate for TSD among Jewish Americans of Ashkenazi extraction is about 1 in 30. Extensive counseling and carrier-screening programs reduced the incidence of TSD by 90%.
Sandhoff Disease (β-Hexosaminidase β-Subunit Deficiency)
The age of onset, duration, neurologic symptoms, and ophthalmologic signs in patients with Sandhoff disease are identical to those seen in TSD, but mild hepatosplenomegaly (secondary to storage of globoside) and bony deformities may rarely be present. Deficiencies of both hexosaminidase A and B are present. A juvenile-onset variant occurs after age 1 year, beginning with clumsiness and gait ataxia, later dystonic posturing and seizures, but no cherry-red macula. Adult-onset patients follow a similar clinical course to chronic late-onset adult forms of Hex A deficiency.
FIGURE 574-1. Cherry-red macula noted in patient with Tay-Sachs disease.
GM2-Activator Deficiency
Individuals with GM2-activator deficiency have disease course similar to those with infantile-onset TSD or B variant. The storage of glycolipids and the pathologic features are also identical to that found in infantile TSD.
MRI in GM2 gangliosidoses demonstrates atrophy with widening of cerebral sulci, increase in ventricular size, and hyperintensities in the basal ganglia, thalamus, and cerebral cortex. Treatment is limited to symptomatic and supportive care. Attempts at enzyme replacement therapy were unsuccessful, owing to problems with the delivery of the enzyme to the CNS. The experience in treating patients with bone marrow transplantation is very limited.
FABRY DISEASE
Fabry disease is an X-linked condition resulting in lysosomal accumulation of various glycosphingolipids with terminal α-galactosyl residues in the cells throughout the body. It is caused by deficiency of the enzyme α-galactosidase A. In affected hemizygous males, enzyme activity is less than 1% of normal.
Clinical Presentation
Clinical symptoms begin in late childhood or adolescence with periodic crises of pain in the extremities, vascular cutaneous lesions (angiokeratomas), hypohydrosis, corneal and lenticular opacities, strokes, left ventricular hypertrophy, and renal insufficiency. The gene encoding α-galactosidase A (GLA) is localized to Xq22.1. The incidence of Fabry disease has been estimated at 1 in 55,000 male births.
The most debilitating symptom of Fabry disease is pain in the extremities of 2 types: painful crisis and constant discomfort. The painful crises often begin in childhood or adolescence, last from minutes to several days, and may be accompanied by fever and increased erythrocyte sedimentation rate. They are described as intense burning or lancinating pain felt initially in palms and soles, but frequently radiating to proximal extremities and other body parts. In addition to intermittent crises, many patients complain of mild persistent numbness and paresthesias in hands and feet (acroparesthesia). Autonomic nervous system dysfunction manifests as hypohydrosis and anhydrosis (occasionally hyperhidrosis), constipation, chronic diarrhea, and nausea.
Cerebrovascular manifestations include hemipareses, vertigo, diplopia, dysarthria, nystagmus, headache, ataxia, memory loss, and hemisensory loss. Angiography may reveal tortuosity of brain vessels. Cardiovascular manifestations consist of left ventricular hypertrophy due to the deposition of storage material, mitral valve insufficiency, arrhythmias, and electro cardiographic changes. Progressive glycosphingolipid accumulation in the kidney results in the development of azotemia and renal insufficiency. Urinary sediment contains casts and “Maltese crosses,” which are birefringent lipid globules. Gradual deterioration of renal function leads to death in the third to fifth decade unless treatment with chronic hemodialysis or renal transplantation is provided. Angiokeratomas appear as clusters of ectatic blood vessels, dark-blue or black-blue, in the superficial layers of the skin. These lesions are flat or slightly raised and do not blanch with pressure. Usually, they are located in the groin, buttocks, upper legs, and umbilical region (Fig. 574-2). They appear in childhood and gradually increase in number and size over the years. Corneal opacity, which can be seen only by slit-lamp examination, is usually the first ocular abnormality and is present in essentially all hemizygous Fabry patients and most heterozygous females. Lenticular opacities may occur in approximately 30% of affected males and consist of granular anterior capsular and subcapsular deposits or a characteristic posterior capsular opacity (Fabry cataracts). The corneal and lenticular opacities do not interfere with vision. Heterozygous females may have mild symptoms but sometimes can have severe manifestations, similar to affected males, related to a nonrandom chromosome X inactivation. In approximately 30% of females, a few angiokeratomas may be present in the characteristic locations, and intermittent pain and paresthesias may occur; rarely, cardiac and renal symptoms develop.
MRI shows hyperintensity in the periventricular white matter early in the disease and development of subcortical and cortical strokes over time. There is also a characteristic “pulvinar sign” seen in many male patients, which consists of an increased signal intensity on T1-weighted MRI images in the pulvinar nucleus of the thalamus.1 Nerve conduction studies reveal an elevated threshold to current perception but no changes in nerve conduction velocities.
Diagnosis and Treatment
Diagnosis is confirmed by low activity of α-galactosidase A in leukocytes in affected males. In females, measurement of enzyme activity is unreliable, as many carrier females have normal levels. GLA is the only gene known to be associated with Fabry disease, with almost 100% of affected males having an identifiable mutation. Molecular genetic testing is the only reliable method that should be used to identify affected females.
FIGURE 574-2. Angiokeratomas on the abdominal wall of a patient with Fabry disease. (Source: Wolff K., Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ: Fitzpatrick’s Dermatology in General Medicine, 7th edition: http//www.accessmedicine.com)
Carbamazepine, gabapentin, and diphenylhydantoin are used to reduce frequency and severity of periodic crises of excruciating pain. Chronic hemodialysis and renal transplantation are often required when end-stage renal disease is present. Enzyme replacement therapy (ERT) with Fabrazyme (agalsidase beta) has been approved by the FDA and should be initiated as early as possible in all males with Fabry disease, including children and patients with end-stage renal disease. Chaperone therapy, an approach aimed to protect and enhance residual enzyme activity by protecting it from misfolding, is under investigation.
GAUCHER DISEASE
Gaucher disease (GD) is an autosomal recessive disease that results from deficiency of the lysosomal enzyme glucocerebrosidase (also termed β-glucosidase, glucosylceramidase), which leads to accumulation of the glycolipid glucosylceramide in the macrophage-monocyte system throughout the body. Clinical classification is used for determining prognosis and treatment approach. Three major clinical types are determined by absence or presence of CNS involvement: type 1, nonneuronopathic; type 2, infantile onset, acute neuronopathic; and type 3, chronic neuronopathic. Type 1 nonneuronopathic disease does not manifest any neurologic symptoms and often presents in childhood because of massive hepatosplenomegaly. This is the most common form of GD, seen mainly in the Ashkenazi Jewish population. Patients with this form frequently develop osteopenia, lytic or sclerotic bone lesions, and osteonecrosis. Although they do not have primary CNS involvement, neurologic complications may occur secondary to bone disease (eg, spinal cord or root compression due to vertebral disease).
Clinical Presentation of Gaucher Disease (GD) Affecting the Nervous System
Type 2 (acute neuronopathic) disease is a rare condition presenting in infancy with dramatic brainstem findings, including retroflexion of the neck, opisthotonus, spasticity, strabismus, and trismus. Massive splenomegaly and, to a lesser extent, hepatomegaly are present early in the course. These children become symptomatic usually before 6 months and, because of severe brainstem involvement, frequently die by the age of 2 years. Patients with severe neonatal form may present with hydrops fetalis and/or congenital ichthyosis.
Patients with type 3 GD (chronic neuronopathic) have onset of symptoms ranging from early life to preteen years and may survive into the third and fourth decades. Oculomotor apraxia and problems with saccadic initiation are common features and occasionally may be the only neurologic sign. Generalized and myoclonic seizures are common. Dementia and ataxia are observed in the later stages of the disease.
Patients with types 2 and 3 GD have nerve cell loss and neuronophagia, primarily in brainstem, cerebellum and spinal cord. The presence of Gaucher cells, specialized cells containing glucosylceramide, has also been recorded from these areas, correlating with the accumulation of glucosylceramide in the brain. These are lipidengorged cells with characteristic fibrillary appearance to the cytoplasm and eccentrically placed nuclei, derived from a monocyte-macrophage system, distributed throughout the body, and found in spleen, liver, bone marrow, and lymph nodes (Fig. 574-3).
Patients with GD, including type 3, do not have evidence of lysosomal storage upon examination of skin. Bone marrow aspirates show typical Gaucher cells. Diagnosis may be confirmed through the biochemical study of glucocerebrosidase activity on peripheral blood leukocytes. The gene locus for GD is mapped to 1q21. One subgroup of patients with type 3 GD is a genetic isolate from the Norrbotten region of Sweden. It appears that a single founder dating back to at least the 16th century explains the high incidence in this population. Atypical GD due to saposin C deficiency shows phenotypic similarities with neuronopathic GD2 and maps to 10q22.1.
Splenectomy had been used in the past to avoid complications of splenic enlargement in type 1 and 3 GD but is rarely used today because of the increased glycolipid deposition in bone and lung seen following splenectomy. Enzyme replacement therapy with recombinant glucocerebrosidase (Imiglucerase, Cerezyme), used with success for treatment of GD type 1, is effective in reversing the visceral and hematologic manifestations of the disease. It appears that in patients with type 3 GD, enzyme replacement therapy reduces glucosylceramide levels in blood and causes a regression of systemic symptoms with stabilization, but not reversal, of neurological deficits.3 Another type of treatment is substrate reduction therapy. The oral agent miglustat (Zavesca), an iminosugar that inhibits glucosylceramide synthase, is the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. Inhibition of this enzyme reduces production of glucocerebrosides, allowing the residual activity of the glucocerebrosidase, deficient in GD, to be more effective.4 Application of small molecules that act as a chaperone increasing residual activity of the lysosomal enzyme (enzyme-enhancing therapy) may represent a future option for patients with GD.3
NIEMANN-PICK DISEASES
Niemann-Pick (NP) disease is not a single disease, but consists of 2 genetically distinct disorders. Because of the historical background, these diseases are likely to continue to be included together. NP types A and B are caused by an auto-somal recessive deficiency of the gene that encodes the enzyme acid sphingomyelinase, needed to degrade sphingomyelin. NP type A is associated with severe hepatosplenomegaly and infantile-onset neurologic presentation. NP type B is a slowly progressive disorder that does not appear to affect the nervous system to a great extent. The biochemical defect in NP type C patients is an abnormality in cholesterol transport, which leads to accumulation of sphingomyelin and cholesterol and secondary reduction of acid sphingomyelinase activity with some sphingomyelin storage.
Niemann-Pick Type A
Niemann-Pick type A is fatal disorder of infancy. Patients present at around age 3 to 4 months with severe vomiting, diarrhea, and failure to thrive. Striking hepatosplenomegaly, which may be present in the neonatal period, rapidly develops. There are no dysmorphic features or skeletal abnormalities. Brownish or ochre pigmentation of the skin may be observed. By 6 months of age, psychomotor retardation becomes evident. The child demonstrates hypotonia, muscular weakness, progressive loss of acquired motor skills, loss of interest in surroundings, and reduction in spontaneous movements. Axial hypotonia and pyramidal signs are usual features. The disease progresses to severe cachexia, blindness, dysphagia, and rigidity. Macular cherry-red spot may be found in about half of the cases. Seizures usually present at the later stages of the disease. Recurrent pulmonary infections are common, and respiratory failure is usually a cause of death between 1.5 and 3.0 years of age.
FIGURE 574-3. Gaucher cells in Gaucher disease. The two macrophages are engorged with glucocerebroside. (Source: Lichtman MA, SHafer MS, Felgar RE, Wang N: Lichtman’s Atlas of Hematology: http://www.accessmedicine.com)
The diagnostic finding is a low level of acid sphingomyelinase activity in peripheral blood lymphocytes or cultured skin fibroblasts. Bone marrow aspiration shows characteristic lipid-containing “foamy” macrophages, and vacuolated lymphocytes are present in peripheral blood smears. MRI and EEG may be abnormal but typically are not diagnostic. The gene encoding sphingomyelinase is located on human chromosome 11p15.1-15.4.
Treatments are primarily symptomatic. Hematopoietic cell transplantation and gene therapy for NP type A are under investigation and enzyme replacement for NP type B is currently in phase I studies in patients.
Neimann-Pick Type B
Niemann-Pick (NP) type B is also caused by acid sphingomyelinase deficiency but, in contrast to NP type A, patients with NP type B have minimal or no nervous system involvement; thus, type B is called a nonneuronopathic form of the disease (see Chapter 161).
Niemann-Pick Type C
Niemann-Pick type C (NPC) is not an allelic variant of NP types A and B, but a separate disease not involved in sphingomyelinase metabolism. It is caused by a unique error in cellular trafficking of exogenous cholesterol that leads to lysosomal accumulation of unesterified cholesterol. The prevalence of NPC in Western Europe is estimated to be 1/150,000 of live births, more frequent than NP types A and B combined. Two genetic isolates have been described: French Acadians in Nova Scotia (former NP type D) and Spanish Americans in southern Colorado. In these populations the incidence is higher.
Neonatal Onset Approximately 50% of neonates affected with NPC are asymptomatic; in the remaining cases, liver disease is the major sign. Ultrasound examination in late pregnancy may reveal fetal hydrops (rarely) and fetal ascites (more frequently). Prolonged neonatal cholestatic jaundice associated with progressive hepatosplenomegaly is present in about half of the cases. About 10% of the cases may progress into rapidly fatal liver failure. Children with this dramatic, “acute” neonatal, cholestatic, rapidly fatal form die before age 6 months but do not show neurologic symptoms. In children who survive, hepatosplenomegaly may not be detectable later in childhood. Absence of hepatosplenomegaly never eliminates the diagnosis of NPC. Rare cases with severe neonatal respiratory failure due to infiltration of lungs with foam cells have been described. Most cases of NPC are the late-infantile and juvenile neurologic onset forms. In children 3 to 5 years of age, manifestations consist of an ataxic gait, dystonia, and choreoathetoid movements in addition to hepatosplenomegaly. In children 6 to 12 years, poor school performance and impaired fine-motor movements are usually the first symptoms. Seizures or cataplexy may occasionally be the presenting symptom. Cataplexy, which may be accompanied by narcolepsy, is a common sign. Polysomnographic and biochemical studies have demonstrated abnormal sleep and reduction in CSF hypocretin levels, suggesting that the disease may affect hypothalamic secretion of hypocretin.5 The most characteristic sign of NPC is supranuclear vertical gaze palsy, which could be an early manifestation. Children may lose the ability to look downward, upward, or both. Parents may notice compensatory head thrust when the child wants to look downward or upward. In late stages, horizontal saccades may also be impaired. Severe cell loss has been reported in the rostral interstitial nucleus of the medial longitudinal fasciculus (a premotor area of vertical gaze), with lesser degeneration in the paramedian pontine reticular formation, the corresponding center for horizontal saccades.6 As the disease progresses, pyramidal signs and spasticity usually develop. Many patients die in their teenage years from aspiration pneumonia. Adolescent and adult onset may present with features described in the previous section, but with a slower rate of progression. Older patients may present with psychiatric symptoms mimicking depression or schizophrenia.7
The most common gene for NPC, called NPC1, is mapped to chromosome 18q11 and accounts for at least 95% of cases. About 4% of patients have mutations in NPC2 gene, mapped to chromosome 14q24.3. In some patients with the typical clinical and biochemical phenotype, mutations have not been found in NPC1 or NPC2. More than 100 mutations were described in the NPC1 gene, but genotype-phenotype correlations are poor. MR and CT scans may be normal or show cerebellar or cortical atrophy. The severe infantile form is characterized by white matter changes. The diagnosis is confirmed by biochemical testing demonstrating impaired cholesterol esterification and positive filipin staining (a probe forming specific complexes with unesterified cholesterol) in cultured fibroblasts. Molecular genetic testing is available on a clinical basis to confirm the diagnosis. Foam cells and sea-blue histiocytes may be present in bone marrow. Sphingomyelinase activity is often partially deficient in cultured skin fibroblasts, but normal in leukocytes.
There is no specific treatment for NPC. Liver transplantation and bone marrow transplant were attempted but did not slow progression of neurologic symptoms. Most promising was the trial of miglustat, a small immunosugar molecule that reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis.8 Miglustat can improve or stabilize several clinical markers of NPC, such as impairment of voluntary eye movements, swallowing ability, auditory acuity, and deterioration of ambulation index.
NEURONAL CEROID LIPOFUSCINOSES
Neuronal ceroid lipofuscinoses (NCLs) are a group of progressive hereditary neurodegenerative disorders characterized by the accumulation of autofluorescent material rich in lipid, protein, and carbohydrates in the lysosomes. Although lysosomal accumulation is present in all tissues, only neurons are affected. The incidence of NCL ranges in different countries from 0.1 to 7/100,000 live births. The common name Batten disease strictly refers to juvenile-onset NCL (Batten-Spielmeyer-Vogt disease), but is used sometimes to describe all NCLs.
NCLs may be divided into 4 major groups based on age of onset: infantile neuronal ceroid lipofuscinosis (INCL), late infantile neuronal ceroid lipofuscinosis (LINCL), juvenile neuronal ceroid lipofuscinosis (JNCL), and adult neuronal ceroid lipofuscinosis (ANCL). Late infantile neuronal ceroid lipofuscinosis includes classical cLINCL; Finnish variant fLINCL; vLINCL variant, seen predominantly in patients of Portuguese, Indian, Pakistani and Czech/Gypsy ancestry; and Turkish variant tLINCL. Congenital form has been described.9 A separate form is referred to as Northern epilepsy. The NCLs have an autosomal recessive mode of inheritance, with the exception of adult neuronal ceroid lipofuscinosis, which may be inherited in either an autosomal recessive or dominant manner.
NCLs are characterized by progressive neurodegeneration, with cognitive and motor dysfunction, seizures, and vision loss. Infantile form is characterized by normal development until age 6 to 12 months. After that age, developmental arrest and regression become apparent. Patients develop ataxia, myoclonic jerks, and occasionally generalized seizures. Vision loss progresses to blindness at age 24 months. Microcephaly is a uniform feature. Most patients die at age 6 to 7 years. Patients with classical late infantile NCL present between ages 2 and 4 years. Seizures, both generalized tonic clonic and myoclonic, are the most prominent feature and are followed by developmental arrest and regression. Vision loss is slow, but blindness eventually develops. Death occurs at age 10 to 15 years. The leading symptom of juvenile NCL is visual impairment, which usually appears between ages 4 and 7 years. Funduscopic examination reveals macular degeneration, retinal degeneration, and optic atrophy. Visual impairment is followed by behavioral/psychiatric problems, sleep disturbance, and seizures. Most patients survive into their late 20s and 30s. In adult neuronal ceroid lipofuscinosis (Kufs disease), initial signs and symptoms usually appear around age 30, with death occurring about 10 years later.
EEG in neuronal ceroid lipofuscinoses shows slowing and large-amplitude polyphasic spikes elicited by low rates of photic stimulation. Visual evoked potential tests show enlarged early component (“giant” waves). Electroretinogram (ERG) is usually abnormal and ERG responses may become undetectable in advanced stages of the disease. MRI shows progressive cerebral atrophy with bilateral periventricular T2 hyperintensities.
NCLs are now classified on the basis of molecular findings (Table 574-1). Several NCL forms overlap. Late infantile NCL is most commonly caused by mutations in the tripeptidyl peptidase 1 (TPP1) gene, but may also be produced by mutations in the palmitoyl-protein thioesterase 1 (PPT), CLN5, CLN6, CLN7, and CLN8 genes. Adult neuronal ceroid lipofuscinosis may result from mutations in the CLN3 and PPT genes.
Storage material (lipopigment) is typically found in sweat glands, conjunctiva, and other tissues revealed by electron microscopy. Granular osmophilic deposits (GROD) are found in infantile neuronal ceroid lipofuscinosis, predominantly curvilinear bodies in late infantile neuronal ceroid lipofuscinosis, and fingerprint inclusions (eFig. 574.1 ) in juvenile neuronal ceroid lipofuscinosis.
In the past, diagnosis was based on a finding of abnormal material (lipopigment) on skin, conjunctival, or rectal biopsy. Current testing strategy includes testing of enzyme activity of palmitoyl-protein thioesterase 1 (PPT) and tripeptidyl peptidase 1 (TPP1) depending on the age of presentation and targeted mutation analysis. These 2 lysosomal enzymes were found to be deficient in neuronal ceroid lipofuscinoses, and their activity can be measured on leukocytes, lymphocytes, and fibroblasts.
Table 574-1. Neuronal Ceroid Lipofuscinosis Variants
Therapy for all forms of neuronal ceroid lipofuscinose is mostly symptomatic and consists of generalized care and treatment of seizures with anticonvulsants. Promising new therapies are being investigated, including chaperone therapy, stem cell therapy, and CNS vector-mediated gene therapy.10 A recent report suggests that intracerebral gene therapy with the AAV2 vector containing the CLN2 gene demonstrated a reduction in cognitive decline in an open-label 10-patient phase I trial.11
FARBER DISEASE
Farber lipogranulomatosis is an autosomal recessive disease caused by deficiency of lysosomal acid ceramidase, with accumulation of ceramide in the lysosomes. The classical form is characterized by a triad of symptoms: subcutaneous nodules, particularly around joints; painful and progressive joint deformity; and hoarseness secondary to laryngeal involvement. Nodules have also been described in conjunctiva, the external ear, nostrils, and mouth. Seizures and psychomotor retardation/decline are characteristic for most cases. The macular cherry-red spot may be observed.12 Illness is progressive and causes death in the first few years of life. Involvement of subcutaneous tissues is explained by the fact that ceramide plays an important role in normal skin, contributing to lipids that preserve the water permeability of skin. Ceramide metabolism is active in the brain, and thus neuronal storage leads to CNS involvement. The gene for Farber disease is localized to 8p22-p21.3. Bone marrow transplantation was attempted in a patient with classic Farber disease without significant success.13
LYSOSOMAL DISORDERS CONTAINING SIALIC ACID
SIALIDOSIS
Sialidosis is a rare autosomal recessive inherited disorder resulting from a deficiency of α-neuraminidase. Most common is an adolescent-onset form, sialidosis type I, referred to as cherry-red spot myoclonussyndrome. Patients with this form have myoclonic epilepsy and cherry-red macula that typically develops in the third decade; this form is not associated with any significant mental deterioration. Sialidosis type II patients may have a fetal or congenital variant that presents as hydrops fetalis, or a severe infantile onset variant with progressive intellectual retardation, hypotonia, ataxia, sensorineural hearing loss, coarse facies, inguinal hernias, dysostosis multiplex, and cherry-red macula. A subset of GM1 gangliosidosis results from loss of the protective protein cathepsin A, which is required for both β-galactosidase and α-neuraminidase to function; the phenotype that results is similar to the infantile-onset sialidosis. This condition is termed galactosialidosis.
Diagnosis of sialidosis can be made by excess protein-bound sialic acid in urine. Definitive testing requires the analysis of α-neuraminidase enzyme activity in leukocytes or cultured fibroblasts, or both α-neuraminidase and β-galactosidase in the case of galactosialidosis. The gene for α-neuraminidase has been mapped to 6p21.3, and mutations identified. No specific therapies are available.
SIALIC ACID STORAGE DISORDERS
Salla disease and infantile free sialic acid storage disease (ISSD) are characterized by the accumulation of free sialic acid in the lysosomes. They are allelic variants of the same disease and are secondary to a defect in the lysosomal trafficking of sialic acid. Infants with infantile free sialic acid storage disease may have onset prior to birth with nonimmune hydrops presentation; they have a fulminant presentation and die during the first year of life. Individuals with Salla disease are severely mentally retarded, but their life span is nearly normal. Hypotonia and ataxia are the leading features. Mild coarsening of the features without skeletal changes is typical. Diagnosis is based on increased excretion of free sialic acid in urine and presence of vacuoles in skin and leukocytes. The gene for Salla disease and infantile free sialic acid storage disease was mapped to 6q14-15. No specific treatments are available at present.
Molybdenum cofactor is required for the function of 3 enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. In patients with molybdenum cofactor deficiency, activity of all 3 enzymes is diminished. Both isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are autosomal recessive traits. Patients with isolated sulfite oxidase deficiency have a clinical phenotype similar to that of patients with molybdenum cofactor deficiency. The pathogenesis of the brain damage in these disorders is not known, but it may be caused by sulfite accumulation or lack of sulfate in the CNS. Patients present in the neonatal period with refractory convulsions and severe global developmental delay. Imaging findings are similar to those seen in hypoxia/ischemia and consist of cerebral edema, atrophy, dilated ventricles, calcifications, and cystic encephalomalacia. Clinical features also include facial dysmorphology with narrow bifrontal diameter and deep-set eyes, lens dislocation, abnormal muscle tone, opisthotonus, and myoclonus, with associated feeding and respiratory difficulties. Both disorders are fatal and most patients die in early infancy. The diagnosis should be suspected if urine dipstick is sulfite positive. Urinary thiosulfate can be measured and, if elevated, is diagnostic for both sulfite oxidase deficiency and molybdenum cofactor deficiency. Patients with molybdenum cofactor deficiency may have low plasma uric acid level, whereas the level is normal in those with isolated sulfite oxidase deficiency. Some success was achieved by placing 2 patients with isolated mild sulfite oxidase deficiency on a low-protein diet, with the addition of a synthetic amino acid mixture without sulfur-containing acids cystine and methionine.14