Dr. Mamta Muranjan*
Associate Professor of Pediatrics and Genetics, Department of Pediatrics KEM Hospital, Parel, Mumbai 400012. Email:*
Neurodegenerative disorders are a group of disorders of diverse etiology and variable clinical spectra. At the Genetic Clinic of KEM Hospital, Mumbai neurodegenerative disorders comprise 30-40% of all referrals. The etiology includes heredodegenerative disorders such as Huntington disease, Parkinson's disease and Friedreich ataxia as well as inherited metabolic disorders. Complexity of neurodegenerative disorders lies in the large number of disorders, the wide range of manifestations and variations in age of onset. Amongst the metabolic disorders, organelle disease are an important group. These include lysosomal storage disorders (LSD), peroxisomal disorders and mitochondrial diseases. Though LSD are individually rare, their collective incidence is 1 in 7,700. Diverse manifestations and overlapping clinical phenotypes of these disorders make clinical diagnosis a challenge. The symptoms mimic those of acquired/environmental agents like slow virus disease or chronic encephalopathy.

Primary defect is a mutation of the gene coding for an enzyme or protein involved in the biosynthesis or degradation of complex molecules. In LSD deficiency, lysosomal or non-lysosomal proteins produces a metabolic block. As a consequence of metabolic block, undegraded or partially degraded substrates accumulate within the lysosomes. The lysosome enlarges and causes progressive cellular dysfunction. The brain is the principle organ involved in almost all disorders. Progressive neuronal dysfunction is evident clinically as a course distinguished by neurodegeneration i.e., deterioration from a previous level of functioning. A child progressively lags behind his peers in acquiring new milestones. Eventually a plateau phase is reached when no new skills are attained and typically this is followed by frank regression. With options of treatment being available for a few diseases and the therapy for additional diseases in the pipeline, it is challenge for physicians to diagnose treatable disorders at an early age before manifestations of brain dysfunction so that therapy provides optimum benefits.

A detailed clinical history, meticulous examination and a logical approach is most often rewarding. This includes carefully obtaining obstetric and family history. Pathologic features have been demonstrated in the fetal brain and clues such as non-immune fetal hydrops, bone abnormality, hepatosplenomegaly or increased nuchal translucency should arouse suspicion of LSD. In most families birth of an affected child is the first evidence, though most families are unaware of their risk for having an offspring with a metabolic disorder.

Clues such as non-immune fetal hydrops, bone abnormality, hepatosplenomegaly or increased nuchal translucency should arouse suspicion of LSD.

Sometimes a history of similarly affected siblings is available. Some of these disorders eventually cause death, so the affected sibling is often not available for examination and medical records/reports are not preserved. The likelihood of having children with a genetic disease is higher with consanguinity and in in-bred communities. This is because, with few exceptions, these disorders demonstrate an autosomal recessive pattern of inheritance. Disorders with X-linked recessive inheritance are Adrenoleukodystrophy. Menkes' disease, Lesch-Nyhan syndrome, Hunter disease, Fabry's disease and Pelizaeus Merzbacher disease. Rett syndrome follows an X-lined dominant pattern while Huntington disease is autosomal dominant. The postnatal age of manifestation is variable. (Table 1) This reflects in part the rate of derangement of neurological function from ongoing disease process. There is evidence of genotype-phenotype correlation for severity of manifestations and the age of presentation. An example is Gaucher disease where the N370S mutations predicts the relatively milder, adult onset type 1 disease whereas the L444P mutation in a homozygous state results in the severe infantile onset neuronopathic disease.

Table 1: Age of onset of some common Diseases

Age group


Neonatal <1 month

Galactosialidosis, GM, gangliosidosis, I-cell disease, Wolman disease, Zellweger syndrome.

Early infantile 1-12 months

Alexander's disease, Biotinidase deficiency, Canavan disease, Gaucher type II, GM 1 gangliosidosis, I-Cell disease, Krabbe disease, Menkes disease, Niemann Pick type A, Tay-Sachs disease.

Late infantile 1-4 years

Ataxia telangiectasia, Gaucher type III, GM 1 gangliosidosis, GM 2 gangliosidosis, Infantile neuronal ceroid lipofuscinosis, Krabbe disease, Metachromatic leukodystrophy, Niemann-Pick type C, Sanfilippo (MPS type III).


Adrenoleukodystrophy, Friedrich ataxia, Gaucher type III, GM 1 gangliosidosis, GM 2 gangliosidosis, Huntington chorea, Hallervorden Spatz disease, krabbe disease, Leigh disease, Metachromatic leukodystrophy, Neuronal ceroid lipofuscinosis, Niemann-Pick type C, Wilson disease.

The basic steps in the clinical approach to an individual with a suspected neurodegenerative disease are:
  • Establish the neurodegenerative nature of the disorder
  • Determine the age of onset
  • Determine the course of the disease: Is it acute, intermittent or chronic?
  • Elicit the symptoms and signs
  • Determine whether symptoms predominantly reflect grey matter disease or white matter disease.
  • Determine the pattern of involvement: is the CNS involved alone or with the peripheral nervous system.
  • Search for extra-neurological manifestations
  • Ensure that the symptom complex cannot be attributed to an extrinsic (environmental) event.

Most early symptoms are subtle and non-specific. It is when the disease is fairly advanced that the signs become overt and this is the time when most individuals are brought to medical attention (Table 2).

Table 2: Common Symptoms of LSD
Neurological 1 manifestation

Age group

Early infantile Late infantile Juvenile
Psychomotor Regression/ Dementia Deteriorating scholastic performance

GM 1 gangliosidosis GM 2 gangliosidosis Menke's diseaseNiemann-Pick disease type A I-cell disease

Niemann-Pick disease type C Neuronal ceroid pofuscinosis Rett syndrome

Sanfilippo disease MLD Krabbe disease Juvenile GM 1 and GM 2 gangliosidosis Niemann-Pick disease type C Gaucher type III

Paraplegia/ quadriplegia Pseudobulbar palsy

Gaucher type 2 GM 1 gangliosidosis

MLD Krabbe disease Neuroaxonal dystrophy

Niemann-Pick disease type C Gaucher type III MLD Adrenoleukodystrophy Leigh disease Krabbe Juvenile GM 1 and GM 2 gangliosidosis


Phenylketonuria GM 2 gangliosidosis Canavan disease Alexander diseaseKrabbe disease

Gaucher type III Niemann-Pick type C Neuronal ceroid lipofuscinosis Alpers disease

Gaucher type III Niemann-Pick type C Neuronal ceroid lipofuscinosis GM 2 gangliosidosis Mitochondrial disorders

Extrapyramidal symptoms Choreoathetosis Dystonia

Lesch-Nyhan syndrome Pelizaeus-Merzbacher disease Glutaric aciduria type I

Ataxia elangiectasia

Wilson disease Hallervorden-Spatz disease Huntington disease Neuronal ceroid lipofuscinosis

Ataxia Leigh disease Ataxia telangiectasia Gauchert Type III GM 1 gangliosidosis GM 2 gangliosidosis rabbe disease MLD itochondrial disease Neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinosis GM 1 gangliosidosis GM 2 gangliosidosis MLD Krabbe disease Mitochondrial diseases Freidrich's ataxia Refsum disease Abetalipoproteinemia

Speech disturbances   Rett Syndrom  ALD
Psychosis   GM 2 gangliosidosis

Wilson disease Sanfilippo disease MLD Krabbe disease Niemann-Pick disease type C Neuronal ceroid lipofuscinosis Hallervorden-Spatz Huntington chorea


Alexander disease Canavan disease GM 2 gangliosidosis Glutaric aciduria type I Krabbe disease


Visual loss

GM 2 gangliosidosis Canavan disease

Krabbe disease Neuronal ceroid

Neuronal ceroid lipofuscinosis


GM 2 gangliosidosis Canavan disease Leigh disease Neuronal ceroid Lipofuscinosis

Krabbe disease Neuronal ceroid lipofuscinosis Respiratory chain disorders


Motor abilities are easier to track than mental skills. Individually signs and symptoms are not diagnostic. For example, myoclonic seizures are present in Tay-Sachs disease, neuronal ceroid lipofuscinosis, phenylketonuria and Alper's disease. At the same time, several different diseases can manifest with similar combination of signs. It is the unique combination of features that leads to the diagnosis. Presence of cherry red spot with hepatosplenomegaly would suggest a diagnosis of Sandhoff disease, Niemann-Pick disease or early infantile GM, gangliosidosis. In such a situation, a search for unique specific features can narrow down the differential diagnosis e.g., macrocephaly and hyperacusis in Sandhoff disease or coarse facial features and dysostosis multiplex in GM, gangliosidosis. Some signs are so pathognomic that a clinical diagnosis can be made with confidence. As in the case of Menkes' disease, sparse, poorly pigmented and steely hair is diagnostic. However, absence of typical signs and symptoms should not preclude a diagnosis. Sometimes initial examination may fail to disclose a characteristic pattern. In such a situation, follow-up visits should be scheduled to detect the evolving pattern.

Symptoms of grey matter involvement result from neuronal dysfunction. Progressive neuronal storage results in neuronal death and secondary axonal degeneration. The pathology of white matter disease is due to a disorder of myelin metabolism that results in destruction of normal myelin (demyelination) or synthesis of a biochemically abnormal myelin, which is degraded rapidly (dysmyelinating disorders or leukodystrophies). (Table 3).

Table 3: Distinguishing features of Grey and White matter disease

Type of involvement

Grey matter disease

White matter disease


Psychomotor regression (infants and young children) Dementia (children older than 4-6 years) Impaired cognition Seizures Loss of speech, dysarthria Extrapyramidal symptoms Ataxia Visual loss Pigmentary retinal degeneration Cherry red spots Hearing impairment

Ataxia Spasticity Early deterioration of motor skills Babinski sign Peripheral neuropathy Blindness Optic atrophy


Tay-Sachs disease Niemann-Pick disease Neuronal ceroid lipofuscinosis Progressive infantile poliodystrophy (Alpers Disease) Menke's disease

Metachromatic leukodystrophy Adrenoleukodystrophy Canavan disease Alexander's Disease CACH syndrome Myelin basis protein deficiency Megalencephalic leukoencephalopathy with subcortical cysts

Presence of characteristic visceral abnormalities almost always point towards a metabolic etiology. These help to distinguish inherited neurodegenerative disorders from acquired diseases with similar symptoms (Table 4).

Table 4: Extra-neurologic signs in neurodegenerative disorders
Visceral Signs

Age group

Early infantile Late infantile Juvenile

Hepato- splenomegaly

GM 1 angliosidosis GM 2 angliosidosis Niemann Pick type A aucher type II

Gaucher type III Niemann-Pick type C

Gaucher type III Niemann-Pick type C


Cherry red spot GM 1 gangliosidosis GM 2 gangliosidosis Niemann Pick type A Sialidosis type II Optic atrophy Krabbe disease
Canavan disease Leigh disease Mitochondrial disorders
Retinitis pigmentosa Abetalipoproteinemia a euronal ceroid lipofuscinosis Infantile Refsum Zellweger syndrome Corneal haze/opacity I-cell disease Zellweger syndrome Mannosidosis

Cherry red spot MLD (rare) Optic atrophy MERRF Neuroaxonal dystrophy MLD Alper's disease
Retinitis pigmentosa Neuronal ceroid lipofuscinosis Corneal haze Mucopolys-accharidosis Mannosidosis Fucosidosis Mucolipidoisis type III, IV Ophthalmoplegia Gaucher type III Neimann-Pick type C Telangiectasia Ataxia telangiectasia

Cherry red spot GM 2 gangliosidosis Sialidosis type I & III Galactosialidosis Optic atrophy renoleukodystrophy Juvenile Krabbe Mitochondrial isease Neuronal ceroid ipofuscinosis Retinitis pigmentosa Refsum disease betalipoproteinemia Hallervorden Spatz Neuronal ceroid lipofuscinosis Mitochondrial disease Ophthalmoplegia Gaucher type III Neimann-Pick type C Mitochondrial disorders
KF Ring Wilson disease

Skin or hair changes

Kinky/steely hair Menkes disease Seborrhoeic dermatitis Biotinidase deficiency Phenylketonuria
Fair skin, blonde hair Phenylketonuria Subcutanenous nodules over joints Farber

Icthyosis - Austin disease Angiokeratomas Fucosidosis Fucosidosis-Galactosialidosis Asparty-lglucosaminuria

Icthyosis - Refsum disease Melanoderma - drenoleukodystrophy Angiokeratoma Fabry disease a Mannosidosis Galactosialidosis

Skeletal abnormalities

Joint swelling Farber
Dysostosis multiplex GM 1 gangliosidosis Arthrogryposis Zellweger Rachitic metaphyses Lowe's disease
Scurvy-like changes - Menkes disease

Dysostosis multipex MPS Mannosidosis Fucosidosis Asparty-lglucosaminuria

Rachitic metaphyses Wilson disease

Facial dysmorphism

Zellweger syndrome Carbohydrate deficient glycoprotein syndrome GM 1 gangliosidosis Coarse MPS Mucolipidosis type III Mannosidosis Fucosidosis  

Presence of characteristic visceral abnormalities almost always point towards a metabolic etiology.

Investigations for LSD include screening tests, diagnostic tests and additional tests like neuroimaging and neurophysiology. Diagnostic tests are biochemical estimation of enzyme activity or substrate quantification and DNA based identification of mutations. Establishing diagnosis by these means is crucial for genetic counseling, prenatal diagnosis and therapy. It must be emphasized that the same phenotype can be caused by different biochemical defects.

Thus a boy with severe cognitive impairment, coarse facies and dysostosis multiplex could have either MPS type I, MPS type II or MPS type VII.

Each of these has a distinct biochemical deficiency: iduronidase, iduronate sulfatase and beta glucuronidase deficiency respectively. Even within a given phenotypic subtype such as MPS type III, there are distinct biochemical phenotypes. Without determining enzyme activity, these cannot be distinguished on the basis of clinical or radiological examination alone. Moreover enzyme replacement therapy (ERT) is available for MPS I (Aldurazyme) and will soon be available for MPS II (Elaplase). In this context confirmed diagnosis is a prerequisite. The tests are selected based on the likely differential diagnosis. These are listed in Table 5. Individual gene mutations have been identified for almost all the metabolic disorders. Some are private mutations (confined to the family) whereas others demonstrate ethnic or geographical specificity.

Table 5: Investigations for Neurodegenerative disorders
Symptom complex Disorder Investigation Tissue

Coarse facies, ysostosis, hepatosplenomegaly, hernias, corneal clouding


Late infancy, childhood
•  MPS, Fucosidosis, Mannosidosis, Aspartylgluosaminuria,
Mucolipidosis, Galactosialidosis

• MPS spot • U
• MPS electrophoresis • U
• GAG quantification • U
• Oligosaccharides • U
 • Enzyme activity • L,F,CVS, AF

Cognitive regression, seizures, macrocephaly

Early infancy (cherry red spot usually present) •  GM 1 gangliosidosis, Sialidosis (Mucolipidosis), Infantile sialic acid Storage disease (ISSD), Galactosialidosis

• Oligosaccharides • U

 •  Sialic acid

• U, F

•  Enzyme activity


Hepatoslenomegaly, anemia •  Krabbe disease
•  Canavan disease
•  GM 2 gangliosidosis Alexanders disease
• MRI/ MRS brain  
• Protein quantification • CSF
• n-acetylaspartate levels

• U and CSF

• Nerve conduction  
• Enzyme activity • L,F, CVS, AF

Extrapyramidal symptoms, hepatitis, portal hypertension, KF ring

•  Gaucher disease
•  Niemann Pick disease •  Wilson Disease

•  Bone marrow examination

• Enzyme activity
• L,F, CVS, AF
• Copper
• U, S, Liver
• Ceruloplasmin  
• Liver biopsy  
Cognitive regression, ataxia, seizures, visual impairment •  Adrenoleukodystrophy •  Neuronal ceroid lipofuscinosis
•  Refsum disease
•  Mitochondrial disorders
•  Subacute sclerosing panencephalitis

•  Lactate

• S

•  Biopsy •Skin, rectal, conjunctival
•  Nerve conduction  
•  MRI  
•  VLCFA •Plasma
•  Cortisol •Plasma
•  Lactate •S, CSF


• Immunoglobulins • S, CSF

Failure to thrive, Strokes, ataxia, visual impairment, cardiac abnormalities

•  Mitochondrial disorders
•  Carbohydrate
• deficient glycoprotein syndrome

•  Transferring isoelectric focusing

Facial dysmorphisms, hypotonia, jaundice, renal and bone abnormalities, visual impairment

Zellweger syndrome


Plasmalogens, phytanic acid, pipecolic acid

• Plasma

Steely hair, hypothermia, seizure, scurvy-like metaphyseal changes, tortuous cerebral arteries

Menke's disease


•Copper •S
• Ceruloplasmin •.S
• Microscopy  

•  MRI, MR Angiography

Supporting investigations Electroencephalogram, electroretinogram, electromyography, nerve conduction studies, Magnetic resonance imaging, magnetic Resonance spectroscopy, DNA study

F: cultured skin fibroblasts, L: leukocytes, CV: chorion villus, AF: cultured amniotic fluid fibroblasts, U: Urine,
S:Serum, MRI: Magnetic resonance imaging, MRS: Magnetic resonance spectroscopy
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