1 st National Conference on Neurogenetics, SESSION : NEURODEGENERATIVE
Dr. G. R. Sethi,
Professor of Pediatrics, Maulana Azad Medical College.
Email : :yogodan@bsnl.com

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Motor Regression is loss of gross motor and/or fine motor skills. The disorders which present with motor regression may initially manifest also as delay / stagnation of development. Problem in diagnosing regression may arise because in many Inborn Errors of Metabolism regression is episodic, worsening with acute illnesses and many acute or chronic severe illnesses are also associated with loss of motor skills. The exact duration after which regression in milestones after an acute illness, is to be taken as significant has not been defined anywhere but any child whose motor abilities don’t improve commensurate with improvement in his / her general condition and / or who has disproportionate changes in tone or loss of skills in association with minor illnesses should be assessed for these disorders and kept under observation.

The causes of motor regression can be classified according to the ‘site of lesion in the Nervous System’ and also according to the ‘Age at presentation’.

Anatomical Site	Clinical features	Examples
Upper Motor Neuron	•  Spasticity •  Brisk tendon reflexes •  Extensor plantar responses •  Weakness in corticospinal distribution	•  Hydrocephalus •  Brain tumors •  Stroke •  Spinal cord-compressive myelopathy •  Degenerative cord disorders hereditary spastic paraparesis
Anterior born cell	•  Hypotonia •  Absent DTRs •  Atrophy •  Fasciculations	•  Hereditary- spinal muscular atrophy •  Acquired- poliomyelitis
Nerve	•  Sensory involvement •  Distal weakness, atrophy, areflexia	•  Hereditary – HMSN, metabolic neuropathies, porphyria •  Acquired – CIDP, GBS, Lead
Neuromuscular junction	•  Fatigable muscle weakness characteristic •  Diurnal variation •  Involvement of extraocular muscle	•  Juvenile myasthenia •  Congenital myasthenia
Muscle	•  Proximal weakness progressive difficulties in climbing stairs, Gower's sign •  Degree of weakness is disproportionate to degree of atrophy	•  Inherited congenital myopathies, muscular dystrophies •  Acquired dermatomyositis, endocrine myopathies e.g., thyrotoxic, steroid myopathy
Basal ganglia	•  Rigidity •  Dystonias •  Involuntary movements tremors, choreoathetosis	•  Wilson Disease •  Idiopathic torsion dystonia •  Hallervorden Spatz disease
Cerebellum	•  Hypotonia •  Ataxia •  Intention tremors	•  Inherited Ataxia telangiectasia Chiari Malformations •  Acquired Cerebellar stroke, cerebellar tumors

But any child whose motor abilities don’t improve commensurate with improvement in his / her general condition and / or who has disproportionate changes in tone or loss of skills in association with minor illnesses should be assessed for these disorders and kept under observation.

Child <3 years of age
Group 1: Progressive walking difficulties related to lesions of central and peripheral motor system-Spastic paraplegia and/or peripheral neuropathy

• Metachromatic Leukodystrophy
• Multiple sulfatase deficiency
• Neuroaxonal dystrophy
• Late infantile Krabbe disease
• Late infantile Leigh’s disease
• HMSN Type III
• SMA II & III
• Familial Spastic paraplegia

Group 2: Unsteady gait-ataxia, involuntary movements:

• Ataxia telangiectasia
• Late-infantile Leigh's syndrome
• Glutaric aciduria
• Dopa responsive dystonia
• Lesch-Nyhan syndrome

Group 3: Intermittent episodes of acute neurological dysfunction (ataxia, lethargy, altered sensorium):

• Defects of mitochondrial beta-oxidation
• Carnitine cycle disorders
• Maple syrup urine disease
• Organic acidemias
• Leigh syndrome
• PDH deficiency

Group 4: Myoclonus, seizures, cognitive impairment, ataxia, eye changes, late motor regression:

• Neuronal ceroid lipofuschsinosis
• Sialidosis Type II
• Alpers syndrome

Group 5: Cognitive regression, visceral, skeletal, somatic involvement:

• Mucopolysaccharidosis,
• Multiple sulfatase deficiency
• Fucosidosis
• Mannosidosis

Motor regression in older child or adolescent
Progressive Spastic paraplegia

• Hereditary spastic paraplegia
• Adrenomyeloneuropathy
• Compressive myelopathy
• Juvenile amyotrophic lateral sclerosis
• HTLV-1
• HIV myelopathy
• Sjogren-Larsson syndrome-Ichthyosis/MR/Spastic diplegia
• Arginase deficiency

Progressive cerebellar ataxias

• Friedreich's ataxia
• Abetalipoproteinemia
• AVED-Ataxia associated with Vitamin E deficiency
• Autosomal dominant spinocerebellar ataxias
• Acquired causes: cerebellar and brainstem tumors, hydrocephalus

Extrapyramidal syndromes

• Wilson disease
• Hallervorden-Spatz disease
• Idiopathic torsion dystonia
• Dopa-responsive dystonia
• Juvenile Huntington disease

Peripheral neuropathies

• HMSN Type 1, 2
• Refsum disease
• Ant horn cell- SMA Type III

Progressive myoclonic epilepsies

• Unverricht-Lundborg disease
• Lafora disease
• MERRF
• Sialidosis Type 1
• Others-juvenile Neuroaxonal dystrophy, Dentatorubral-Pallido Luysian atrophy

Diffuse CNS involvement- dementia, seizures, behavior problems, motor regression

• X-linked adrenoleukodystrophy
• Juvenile Neuronal ceroid Lipofuchsinosis
• Juvenile GM1 & GM2 gangliosidosis
• Gaucher disease Type III
• Niemann Pick disease Type C
• Juvenile MLD
• Juvenile Krabbe's diease

History: A detailed history is most important when trying to assess a child with motor problems. History must be elicited in great details to document:

1. ‘Regression' with progressive loss of milestones vs. ‘Delay' and a static disorder.
2. Age of onset
3. Clinical picture and progression of signs and symptoms
   
4. Some disorders initially have choreoathetosis but later pyramidal signs predominate (Lesch Nyhan Syndrome).
   
5. Some have hypotonia as a manifestation of associated polyneuropathy but later marked spasticity is there (Metachromatic Leukodystrophy, Krabbe Disease).
   
6. Some have diurnal variation in symptoms (Myasthenia Gravis, Dopa Responsive Dystonia)
   
7. The predominant and complete picture of motor manifestations including type, distribution; involvement of cranial muscles / nerves, muscles of respiration and cardiac manifestations.
   
8. Presence of visual, hearing problems and gaze palsies.
   
9. Presence of associated learning disabilities and seizures.
   
10. Any precipitating factors e.g. Acute illnesses-IEMs, Gastroenteritis-IEMS, Hypokalemia;> High protein Diet- IEMs.
    
11. Any factors which improve the symptoms e.g. Rest (Myasthenia), Sleep (Dopa Responsive Dystonia).
    
12. H/S/O headache, enlarging head size (hydrocephalus, slow growing brain tumors)
13. Past History Jaundice (Wilson's disease, Niemann Pick disease), Recurrent encephalopathies or admissions (Inborn errors of metabolism)
14. Family History – A detailed family history should be taken for similar / related illnesses e.g. CP, Unexplained deaths, Myopathies, Retinitis Pigmentosa). A 3 degree pedigree chart should also be made.
15. History of Environmental Exposure to Lead and other toxins should also be elicited.

Investigations are planned keeping in mind our probable diagnosis. It is very important to investigate specially for treatable causes.

1. Blood Investigations –
   
   1. Hemogram –- It may show basophilic stippling, Inclusions in WBCs, Acanthocytosis.
      
   2. Serum Electrolytes –- Potassium levels
      
   3. Serum Ca/ PO 4 / ALP
      
   4. Kidney Function Test (some patient with CRF may present with f/o myopathy)
      
   5. Serum CPK (Dystrophies)
      
   6. TFT
      
   7. BGA
      
   8. Lead Levels
      
   9. Serum Copper and Ceruloplasmin Levels (Wilson's Disease)
      
2. IEM Screen – Urine & Blood
3. Radiology: Skeletal Survey/X-ray Wrist/knees – Rickets, Scurvy, Lead Poisoning, CRF etc. :
   MRI/CT scan-Leukodystrophies, Caudate/Globus pallidus/Putamen/Thalamus involvement,
   Cerebellar hypoplasia/atrophy, Hydrocephalus, Intracranial Space occupying lesions.
4. CSF- Increased Lactate (mitochondrial disorders etc), Increased proteins (MLD, Krabbe dis)
5. EMG- Myopathies, Denervation Atrophy (SMA) etc
6. NCV- Neuropathies and some leukodystrophies
7. EKG & Echo Cardiac Involvement
8. Muscle Biopsy
9. Nerve Biopsy- Neuropathies, Leukodystrophies
10. Others- B/M/A in Niemann Pick disease, Skin/Conjunctival Biopsies, Increased VLCFAs in
    Adrenoleukodystrophies, Neostigmine Test For Myasthenia Gravis.
11. Enzyme studies and Mutation analysis wherever available
12. Response to Treatment- Dopa Responsive Dystonia.

1st National Conference on Neurogenetics - Conference Abstracts.Pediatric Oncall [serial online] 2007 [cited 15 February 2007(Supplement 2)];4. Available from:
http://www.pediatriconcall.com/fordoctor/Conference_abstracts/
NEUROGENETICSDEL/child.asp