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Hematopoietic stem cell transplantation HSCT alleviates a number of symptoms of peripheral FD disease but does not prevent progressive neurological deterioration. In most patients, muscle weakness manifests within 1—10 years, followed by the development of seizures. Disease severity and progression varies significantly between patients, and some patients with SMA-PME also develop hearing loss, action tremor, cognitive impairment and cerebral atrophy.

For example, knockdown of the ASAH1 ortholog in zebrafish with a morpholino antisense oligonucleotide leads to increased apoptosis and a marked loss of motor neuron axonal branching in the spinal cord Zhou et al. An aberrant increase in ceramide is also implicated in the pathogenesis of ataxia telangiectasia AT and hereditary sensory neuropathy type 1 HSN1.

AT is an autosomal recessive disease characterized by cerebellar ataxia, telangiectasias, apraxia and progressive neurological deterioration. AT is caused by homozygous or compound heterozygous mutations in the ATM gene, which inhibits DNA damage-induced apoptosis through repression of ceramide synthase Jaspers et al. Cell lines expressing mutant ATM feature enhanced ceramide synthase activity and apoptosis Liao et al. HSN1 is the most common inherited disorder of peripheral sensory neurons that features progressive degeneration of dorsal root ganglia and motor neurons, usually sometime during the 2nd or 3rd decade of life.

Symptoms of HSN1 include sensory loss followed by distal muscle wasting and weakness. HSN1 is associated with mutations in the gene encoding serine palmitoyltransferase long chain base subunit-1 SPTLC1 , the rate-limiting enzyme in de novo ceramide synthesis.

Biological and Medical Aspects

Interestingly, expression of mutant SPTLC1 from affected individuals in lymphoblast cell lines significantly increased GlcCer synthesis, thus suggesting a toxic up regulation of ceramide synthesis Dawkins et al. Disrupted ceramide synthesis is also featured in a number of NMDs, thus suggesting that ceramide levels must be closely titrated to ensure normal motor function.

For example, autosomal recessive mutations in fatty acid 2-hydroxylase FA2H , which catalyzes the hydroxylation of ceramide at position 2 of the N-acyl chain, result in HSP type 35, which is characterized by early-onset progressive spasticity, ataxia, dystonia and cognitive decline Edvardson et al.

Defective FA2H also leads to object neurodegeneration with brain iron accumulation NBIA , a spectrum disorder with phenotypes ranging from infantile with early death to adult-onset parkinsonism-dystonia. Patients with NBIA exhibit cerebellar atrophy, spastic quadriparesis, ataxia, dystonia and episodic neurological decline Kruer et al. A deficiency in ceramide synthesis is also observed in two mouse strains that feature cerebellar ataxia and Purkinje cell death.


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Flincher and toppler mice have spontaneous autosomal recessive mutations in ceramide synthase 1, an enzyme that regulates the de novo synthesis of certain ceramide species Zhao et al. Moreover, a mutation in 3-ketodihydrosphingosine reductase FVT1 , which catalyzes the 2nd step in de novo ceramide synthesis, is associated with bovine spinal muscular atrophy Krebs et al. Ceramide accumulation in the muscle may also contribute to phenotypes found in NMD.

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Collectively, these findings indicate that maintaining ceramide in an optimal homeostatic range or eustasis is important for multiple functional aspects of the neuromuscular axis. Galactosylceramide GalCer is synthesized when galactose is added to the 1-hydroxyl moiety of ceramide. GalCer and its sulfated form, sulfatide, account for approximately one-third of the lipid content in myelin Norton et al.

The high content of galactolipids is believed to provide myelin with its structural stability i. During development, GalCer also modulates the differentiation and maturation of oligodendrocytes, the initiation of myelination and the establishment of axo-glial interactions at the nodes of Ranvier Marcus and Popko, Substrate accumulation in KD leads to the formation of globoid cells, which are large multinucleated macrophages surrounding cerebral blood vessels in white matter, and leukodystrophy, a state of demyelination and gliosis Miyatake and Suzuki, At the cellular level, the recruitment of signaling proteins to lipid rafts is impaired, endocytosis is disrupted and axonal transport is severely compromised during disease Nogueira-Rodrigues et al.

There are both infantile and late-onset forms of KD. Features of infantile KD include irritability, fever, limb stiffness, seizures, difficulty in eating, slowed cognitive and motor development, and growth retardation. The remaining cases of KD have a later onset, commonly differentiated as late infantile 6 months to 3 years , adolescent 3—8 years or adult-onset Wenger et al. Late-onset forms of KD are often clinically heterogeneous and less severe.

For example, these patients appear normal until weakness, spastic paraparesis, vision loss, and cognitive decline become evident Tappino et al. Similar to humans, a deficiency in GALC activity also leads to hypomyelination and lower nerve conduction velocities in mice Potter et al. Galactolipid cacostasis resulting from either impaired galactolipid transport or synthesis is also associated with progressive motor dysfunction.

For example, some of the protein products of genes associated with neuronal ceroid lipofuscinoses NCLs , the most common group of inherited childhood neurodegenerative disorders, appear to modulate the intracellular distribution of GalCer. NCLs are associated with mutations in a number of different genes CLN1—CLN14 that produce protein products that reside within varying cellular locations including the lysosome, ER and the vesicular membranes of the cytosol. Emerging evidence suggests that some of these CLN genes may also contribute to other neurodegenerative diseases.

Several lines of evidence suggest that galactolipid cacostasis may also contribute to the pathogenesis of additional diseases affecting the motor system including ALS, multiple system atrophy MSA , Pelizaeus—Merzbacher disease PMD and Menkes disease.

New strategies for the treatment of lysosomal storage diseases (Review)

The latter finding suggests that galactolipid metabolism is disrupted in multiple cellular organelles in ALS. MSA is a rapidly progressive neurodegenerative disease characterized by Parkinsonism, cerebellar ataxia, autonomic failure, and the accumulation of alpha-synuclein in oligodendrocytes. Recent findings suggest that myelin instability in MSA is associated with a significant reduction in GalCer levels Don et al.

Similarly, both PMD, a leukodystrophy associated with mutations in proteolipid protein 1 Trofatter et al. PMD is an unusual leukodystrophy because it results from the improper formation of myelin rather than from demyelination, the predominant cause of most leukodystrophies. Features of PMD include hypotonia, nystagmus, spasticity, ataxia and the development of choreoathetotic movements later in life. Patients with PMD typically deteriorate slowly until death in mid-adulthood Inoue, Niemann-Pick disease NPD is an eponym referring to a disease in which patients feature varying degrees of lipid storage, hepatosplenomegaly, respiratory impairment and CNS involvement.

NPD is caused by two different metabolic abnormalities. Patients with the type A or type B disease have a deficiency in sphingomyelin phosphodiesterase 1 SMPD1 , also known as acid sphingomyelinase ASM , the lysosomal enzyme that hydrolyzes sphingomyelin to form ceramide and phosphocholine Figure 2 ; Kampine et al. NPD type C patients also have deficiencies in ASM and moderate accumulation of sphingomyelin; however, this is secondary to the defect in cholesterol esterification Pentchev et al.

Type A and type B NPD form a continuum of phenotypes varying from acute neurological to chronic neurological and chronic non-neurological. CNS abnormalities, including hypotonia, motor incoordination, akinesia, spasticity and a loss of deep tendon reflexes, typically manifest between 5 and 10 months of age in NPD type A patients.

Sadly, children typically succumb to the disease prior to their 3rd birthday. Type B is a non-neuropathic form that is diagnosed in late infancy, childhood or even adulthood, with the majority of type B patients living until late adulthood McGovern et al. There are also intermediate forms of the disease that feature delayed neurological onset and a slowly progressive disease course characterized by cerebellar ataxia, extrapyramidal involvement and psychiatric disturbances Pavlu-Pereira et al.

Disease onset varies from neonatal to adulthood, and some patients only live a few days, while others may live into their sixth decade.

Most patients develop a progressive neurological disease that often features cerebellar ataxia, dysarthria, dysphagia, cataplexy, seizures, dystonia, vertical supranuclear gaze palsy and progressive dementia Vanier, Sphingomyelin, the substrate that accumulates to varying degrees in all NPD patients, is a major structural component of plasma membranes, endosomes and lysosomes. Sphingomyelin is also bioactive in numerous cellular processes including membrane trafficking, cellular migration and proliferation, DNA repair and autophagic death Taniguchi and Okazaki, Moreover, sphingomyelin levels are significantly elevated in the substantia nigra of patients with PD Riekkinen et al.

In the brains of MSA patients, sphingomyelin levels are severely depleted in the white matter Don et al.

Lipid Storage Disorders: Biological and Medical Aspects (Nato Science Series A:)

Unesterified cholesterol accumulation in NPD type C disease patients, identified by staining with the polyene antibiotic filipin, is a secondary metabolic defect that is also observed in type A disease patients Sokol et al. Although there are no reports of free cholesterol accumulation in some of the more common diseases of the motor system, cholesterol homeostasis is disrupted in some of these diseases. For example, aberrant cholesterol metabolism is observed in ALS Cutler et al. Glucose derived from glycogen enters the glycolytic pathway to generate pyruvate and subsequently acetyl-CoA, the fundamental building block of cholesterol and fatty acids.

Fatty acids are essential for the de novo synthesis of ceramide, cerebrosides e. Therefore, disruptions in glycogen metabolism may adversely affect lipid synthesis or, alternatively, may manifest when lipid synthesis is down regulated during states of lipid cacostasis. Pompe disease is an autosomal recessive NMD caused by a deficiency in acid alpha-glucosidase GAA , the lysosomal enzyme that catalyzes the hydrolysis of glycogen Figure 2.

GAA is expressed in skeletal muscle, the diaphragm, the heart, the liver, kidneys, and the CNS, in which the highest expression is in neurons of the midbrain, brainstem and the anterior horn of the spinal cord Ponce et al. Delayed myelination and mild cerebroventricular dilation are also observed in infantile-onset Pompe patients Chien et al. The rate of disease progression is much slower in Pompe patients with late-onset disease. However, the disease typically progresses to include limb-girdle muscular dystrophy with diaphragm involvement, eventually leading to wheelchair dependance, respiratory failure and death in adulthood Hagemans et al.

Adult polyglucosan body disease APBD and Lafora disease LD are neurodegenerative disorders that are also directly caused by the aberrant deposition of glycogen.


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The intracellular accumulation of polyglucosan bodies in the PNS and CNS is the pathological hallmark of APBD, a rare autosomal recessive leukodystrophy caused by a deficiency in glycogen-branching enzyme. Clinically, APBD is characterized by neurogenic bladder, progressive pyramidal paraparesis and polyneuropathy. APBD usually manifests in the 5th or 6th decade of life, slowly progressing until the loss of independent walking, often followed by cognitive decline and premature death Robitaille et al.

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LD is a fatal neurodegenerative disease that is caused by autosomal recessive mutations in either laforin phosphatase EPM2a or malin ubiquitin E3 ligase EPM2b , which are proteins that regulate the activity of glycogen synthase. Symptoms of LD include seizures, early learning difficulties, dysarthria, ataxia, visual hallucinations and dementia, all of which worsen over time and typically become intractable by 5 years of age Turnbull et al.

Glycogen levels are elevated in the spinal cords of sALS patients, and interestingly, although acidic GAA activity is not altered, neutral GAA activity is up regulated, thus suggesting that glycogen storage occurs outside of the lysosome during the course of the disease. Interestingly, in a retrovirus-induced mouse model of motor neuron degeneration, glycogen deposition also occurs in the spinal cord Brooks et al.

ZSD is a heterogeneous group of genetic disorders that are caused by mutations in peroxin genes that regulate the assembly and function of peroxisomes. The clinical spectrum of ZSD is complex, ranging from profound neurological symptoms in infants to progressive neurodegeneration in adults. CNS-related symptoms of ZSD include seizures, retinal degeneration, hearing loss, psychomotor retardation, leukodystrophy, cerebellar ataxia and peripheral neuropathy Braverman et al.

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