1 st National Conference on Neurogenetics, SESSION : FLOPPY BABY

Devendra Mishra ,
Assistant Professor of Pediatrics, Chacha Nehru Bal Chikitsalaya, Maulana Azad Medical College, New Delhi.
Email : dr_dmishra@rediffmail.com

Although it was known since the time of Galen that nerves conveyed sensations and motility to extremities, it was only in the 19th century that the functions of the nerves and the pathological states affecting them began to be elucidated. Amongst the hereditary neuropathies, Friedreich first described the eponymous condition bearing his name in 1863; followed by the seminal reports of Charcot and Marie, and Tooth separately in 1886. Dejerine and Sottas described the ‘progressive hypertrophic interstitial neuropathy of childhood' in 1893. Much discussion has centered on the classification and nosology of these conditions since their original description. From 1956 onwards, with the availability of clinical neurophysiological techniques and the subsequent utilization of histological examination of nerve biopsy, it became possible to characterize the peripheral neuropathies more precisely. This led to the classification of hereditary neuropathies given by Dyck in 1975, recently revised in 1993. A more recent classification based on clinical and neurophysiological picture but also incorporating the genotypic data has been recently proposed (Table 1).

HMSN I	Autosomal dominantType a, b with known mutationsType c with unknown mutation
HMSN I	Autosomal recessive With focally folded myelin, with basal lamina onion-bulbs, and with linkage to various chromosomal locations
MSN X	X-linked 1 dominant mutation or deletion at Xq 13.1 2, 3 recessive
HMSN II	Autosomal dominant Type a, b, d, e linkage known Type c unknown
HMSN II	Autosomal recessive Infantile form (often fatal) Axonal type with onset in early childhood
HMSN III*	Variable inheritance
HMSN IV and CMT IV**
HMSN V HMSN VI HMSN VII	With spastic paraparesis With optic atrophy With retinitis pigmentosa
Other rare and complex forms

*The term HMSN III should be restricted to hereditary neuropathies in which hypomyelinatin is the dominant feature.
**Much confusion about this entity. Category may be discarded.
Modified from Ouvrier RA, McLeod J, Pollard JD. Peripheral neuropathy in childhood. International Review of Child Neurology Series. II Edition 1999, MacKeith Press, London.

Very few large series of chronic peripheral neuropathy in childhood have been reported. The various paediatric series differ from adult collections in a number of ways. There is a low incidence of toxic neuropathy and of neuropathy due to systemic diseases such as cancer, diabetes and collagen vascular disease; but a high incidence of inherited neuropathies, including those associated with metabolic diseases and CNS pathology. Going through the published reports, we may conclude that when adequate family studies are combined with detailed investigation of the patient by clinical, neurophysiological and histopathological techniques, the correct diagnosis can be reached in the majority of children with chronic polyneuropathy; and, in most cases, a genetic etiology is found

Symptoms
Most chronic polyneuropathies are symmetrical, predominantly distal and with mixed sensory and motor manifestations. Sensory disturbances may include numbness, tingling, ‘pins and needles' in the hands and feet, burning sensations, pain in the extremities, sensations of walking on cotton wool, band-like constrictions around the wrists or ankles, unsteadiness on the foot and stumbling.

Most chronic polyneuropathies are symmetrical, predominantly distal and with mixed sensory and motor manifestations

Motor symptoms are usually those of weakness, and children may find difficulty in running, walking, undoing buttons and performing fine movements. Muscle wasting, foot drop and wrist drop are common. Foot deformity, particularly pes cavus, is one of the commonest forms of presentation of hereditary neuropathy. Autonomic dysfunction may be manifested as dryness or excessive sweating of the extremities, postural hypotension, diarrhea and constipation.

Foot deformity, particularly pes cavus, is one of the commonest forms of presentation of hereditary neuropathy

The signs are usually those of distal muscle wasting and weakness and impairment of all types of sensation predominantly over distal regions, and often in a ‘glove and stocking' type of distribution Reflexes are usually depressed or absent, but in mild cases the abnormalities may be confined to the ankle jerks since the pathway is longer than that of other reflexes. Visible enlargement of the nerves in the cervical region or palpable thickening of limb nerves may be seen in the hypertrophic forms of hereditary motor and sensory neuropathies (HMSN), leprosy and chronic inflammatory demyelinating polyneuropathy (CIDP).

Most neuropathies have a gradual onset and a slow progression. Acute onset of neuropathy is seen in only a limited number of conditions viz, GBS, Diphtheria, toxic causes, acute porphyria, post-vaccination, critical illness polyneuropathy, and Tyrosinemia (the only hereditary condition). After toxic and metabolic causes have been excluded, in children the most likely categories of chronic neuropathy to be considered are the hereditary neuropathies and CIDP, which may be easily differentiated.

Symmetrical vs. Asymmetrical. Most neuropathies have a symmetrical distribution and affect the lower limbs to a greater extent than the upper limb. Some neuropathies have an asymmetrical presentation and these include the acute and chronic inflammatory neuropathies and those caused by diseases of small blood vessels, usually vasculitis. Mononeuritis multiplex, a form of neuropathy with asymmetrical involvement of individual nerve trunks, is very rare in childhood. It is common with leprosy, vasculitis and diabetes, but may occur with primary and familial amyloid polyneuropathy, sometimes occurring as early as 13 year of age. Proximal vs. Distal. Most peripheral neuropathies characteristically have a distal distribution, but proximal weakness may be a feature of porphyria, acute and chronic demyelinating neuropathies, and Dejerine-Sottas disease. Lower limbs are usually affected earlier and to a greater extent than the upper limbs but exceptions to this rule are acute and chronic demyelinating neuropathies, porphyria and lead poisoning.

Although most peripheral neuropathies have mixed motor and sensory manifestations, some conditions affect mainly motor or mainly sensory fibres (Table 2). When large sensory fibres are predominantly affected there is characteristic impairment of light touch, vibration and position sense with sparing of pain and temperature sensation and loss of reflexes (e.g., Friedreich's ataxia). In some other neuropathies, the small fibres are selectively involved causing autonomic dysfunction, symptoms of burning pain, and loss of pain and temperature sense with relative sparing of tactile sensation (e.g., primary and familial amyloidosis, hereditary sensory and autonomic neuropathies, diabetes).

Predominantly motor	Predominantly sensory
Porphyria	HSAN
Charcot-Marie-Tooth disease	Primary or familial amyloidosis
Recurrent neuropathy	Sjogren syndrome
Refsum disease	Painful neuropathies
Tangier disease	HSAN type I
Acute intermittent porphyria	Krabbe disease
Tyrosinemia, Leigh disease	Fabry disease
Hereditary neuropathy with liability to pressure palsies
Hereditary thermosensitive neuropathy

Given the wide array of investigational modalities available to the present-day clinician, the approach to the investigating a child with peripheral neuropathy, as in any other disease, should be tempered by the history and examination findings. The single most important investigation of a child presenting with evidence of peripheral neuropathy is the examination of the parents and siblings, even if apparently unaffected.

The single most important investigation of a child presenting with evidence of peripheral neuropathy is the examination of the parents and siblings, even if apparently unaffected.

The basic investigations that should be performed in all children with peripheral neuropathy of undetermined cause include urinalysis, full blood count, ESR, fasting blood sugar, serum electrolytes, serum creatinine, serum protein liver function tests and chest X-ray, although they will rarely reveal an etiology. Other investigations that may be performed depending on clues derived from clinical assessment include urinary porphyrins and heavy metals, serum B12 level, urinary amino acids, fecal fat analysis, and other tests for suspected diseases (Table 3). A lumbar puncture with examination of CSF is unrewarding in most cases of axonal neuropathy.

Condition	Investigation
Primary amyloid neuropathy	Rectal, liver, renal, abdominal fat, nerve biopsy; plasma immunoelectrophoresis; urinary Bence-Jones protein
Familial amyloid polyneuropathy	Serum, tissue transerythretin
Metachromatic leukodystrophy	Blood leukocyte, skin fibroblast arylsulphatase
Krabbe disease (globoid cell leukodystrophy)	Blood leukocyte, skin fibroblast galactosylceramide ß -galactosidase
Abetalipoproteinemia	Acanthocytes in blood, serum Plasma LDL and DLDL
Tangier disease	Serum cholesterol, Plasma HDL
Refsum disease	Serum phytanic acid, -oxidation of phytanic acid in skin fibroblasts

Electromyography. EMG should normally be performed in order to differentiate a peripheral neuropathy from a myopathy particularly when there is proximal muscle wasting or weakness. Normally there is no electrical activity recorded at rest, but in nerve injuries and disease spontaneous fibrillations and positive sharp waves may be present. On voluntary effort the number of motor unit potentials is reduced, and in chronic neuropathies, if reinnervation of muscles has occurred, giant motor unit action potentials may be recorded.

These studies should be carried out on all children with suspected peripheral neuropathy. They are useful in confirming the presence of a generalized peripheral neuropathy, indicating whether the underlying pathology is that of axonal degeneration or demyelination and whether both motor and sensory fibres are involved. Hereditary peripheral neuropathies associated with marked slowing of conduction and segmental demyelination are Dejerine-Sottas disease, Charcot-Marie-Tooth disease, metachromatic leukodystrophy, Refsum's disease and Krabbe's disease.

Nerve conduction studies are useful in confirming the presence of a generalized peripheral neuropathy, indicating whether the underlying pathology is that of axonal degeneration or demyelination and whether both motor and sensory fibres are involved.

Autonomic dysfunction is a common complication of peripheral neuropathies although often it is mild and of little relevance. In some conditions, however, there may be profound disturbances of autonomic function including orthostatic hypotension, impairment of blood pressure, and heart rate and bladder control. Diseases that primarily affect small fibres in peripheral nerves or cause acute demyelination of small myelinated fibres are those most likely to cause autonomic dysfunction. These include, among others, familial and primary amyloidosis, Riley-Day syndrome, and some other hereditary sensory and autonomic neuropathies. There are many available tests from which to select; tests of both sympathetic and parasympathetic function should be included and it is generally necessary to find abnormalities in two or more of these tests to confirm the presence of autonomic dysfunction. Tests of autonomic dysfunction that can be undertaken in the clinical neurophysiology laboratory are heart rate variation with respiration, Valsalva ratio, heart rate response to standing or tilting, blood pressure response to sustained handgrip, and the sympathetic skin response.

Tests of both sympathetic and parasympathetic function should be included and it is generally necessary to find abnormalities in tow or more of these tests to confirm the presence of autonomic dysfunction.

If the diagnosis has not been made from electrophysiological and other studies, biopsy of the sural or radial nerve may be helpful. Although DNA or lysosomal enzyme analysis is available for many of these disorders; there may be diagnostic appearance in the nerve biopsy in HMSN (CMT), HSAN, Dejerine-Sottas disease, tomaculous neuropathy, giant axonal neuropathy, Krabbe's disease, Fabry's disease and metachromatic leukodystrophy.

There are now many hereditary neuropathies in which the gene locus has been identified, and the number is continuing to increase. Table 4 shows the important hereditary peripheral neuropathies in which the gene has been identified.

Disease	Chromosome location	Gene product	Genetic defect
CMT Ia (HMSN Ia)	17p11.2-12	PMP22	Duplication; point mutation
CMT Ib (HMSN Ib)	1q21.2-23	P 0	Point mutation
CMT X (HMSN-X)	Xq13	Connexin-32	Point mutation
Hereditary liability to pressure palsies (tomaculous neuropathy)	7p.11.2-12	PMP22	Deletion; point 1 mutation
Familial amyloid Polyneuropathy (most types)	18q11.2-12.1	genes on chromosome plus two unidentified 9 and 11	Point mutation

Therapeutic measures currently available for the neuropathies are often not very effective particularly in childhood, where the basic mechanisms of the many conditions are poorly understood and progression is often irreversible. Therapy may be subdivided into three types; (i) therapy directed to underlying illness if the aetiology is known e.g., Refsum's disease, (ii) improvement of nerve function by therapy directed to improving nerve metabolism itself, (iii) symptomatic therapy. Further, especially in children, judicious use of orthotics and surgery often helps to avoid serious contractures and deformities, which may occur in untreated patients.

1. Ouvrier RA, McLeod J, Pollard JD. Peripheral neuropathy in childhood. International Review of Child Neurology Series. II Edition 1999, MacKeith Press, London.
2. Dyck PJ, Thomas PK, Griffin JW, et al (eds). Peripheral Neuropathy, 3rd edition. Philadelphia: WB Saunders, pp 1094-136.
3. Rocha CT, Escolar DM. Update on diagnosis and treatment of hereditary and acquired polyneuropathies in childhood. Suppl Clin Neurophysiol. 2004;57:255-71.
4. Ryan MM, Ouvrier R. Hereditary peripheral neuropathies of childhood. Curr Opin Neurol. 2005 Apr;18(2):105-10.
5. Chance PF. Genetic evaluation of inherited motor/sensory neuropathy. Suppl Clin Neurophysiol. 2004;57:228-42.
6. Scherer SS. Finding the causes of inherited neuropathies. Arch Neurol 2006 Jun;63(6):812-6.

1st National Conference on Neurogenetics - Conference Abstracts.Pediatric Oncall [serial online] 2007 [cited 15 February 2007(Supplement 2)];4. Available from:
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