Clinical neurology is a vast, complex and confusing area. However, in practice, there are many "clinical patterns" which vastly narrow down the differential diagnosis. Considering this child's history, the frequent falls and difficulty in getting up afterwards are suggestive of lower limb weakness, while the longstanding clumsiness raises suspicion of a hereditary disorder. The above average performance in school suggests that his vision and mental and social development are normal, i.e. that his problems are confined to the motor system. Examination reveals motor weakness of the lower limbs associated with generalized areflexia - this is suggestive of a lower motor neuron pathology. In addition, note that the weakness is symmetric, more distal than proximal, and associated with diminished vibratory sense in the distal lower limbs. This pattern of clinical findings is strongly suggestive of a sensorimotor polyneuropathy. The most common hereditary conditions giving rise to a symmetric mixed polyneuropathy are Friedreich's ataxia and Charcot-Marie-Tooth (CMT) disease. However, chronic inflammatory demyelinating polyradiculopathy (CIDP), metabolic diseases, nutritional deficiencies, neurotoxic medications, infections such as leprosy and even diabetes mellitus may cause an acquired polyneuropathy with similar findings. The simplest option at this point is to perform electrodiagnostic tests to confirm the presence of a polyneuropathy, and if so, determine whether this is an axonal or demyelinating neuropathy. In this patient, the reduction of conduction velocity in both sensory and motor nerves confirms the presence of a sensorimotor polyneuropathy, and points to demyelination as the likely underlying process. At this point, the main differential diagnoses are hereditary conditions and CIDP. The latter should be excluded as it is treatable - a lumbar puncture is suitable in this regard. In this patient, the normal CSF protein level argues against CIDP. The sural nerve biopsy shows a loss of myelinated axons and prominent "onion bulb" formations. This is strongly suggestive of CMT disease of the demyelinating type. The diagnosis is confirmed by the genetic studies showing duplication of the peripheral myelin protein-22 (PMP22) gene, which is seen in CMT type 1A and 1E. Unfortunately, there is no specific disease modifying therapy for CMT disease - management is primarily supportive, with physiotherapy playing a key role. NSAIDs are not indicated in the absence of pain, while there is no role for IV Immunoglobulins or plasmapheresis in his management.
CMT disease (also known as "peroneal muscular atrophy", and "hereditary motor and sensory neuropathy") is the most commonly inherited peripheral neuropathy, affecting individuals of all races and ethnic groups worldwide. Approximately 1 in 2500 individuals in the United States are affected, with a slight female predominance. The modern perception is that CMT is not a single disease entity, but rather a group of chronic peripheral sensory and motor neuropathies with variable genetic causes, patterns of inheritance and penetrance. Four main types have been defined : CMT1 (demyelinating), CMT 2 (axonal degeneration), CMT 3 or Dejerine-Sottas disease (DSD), CMT4 and X-linked CMT (CMT X). CMT1 is the most prevalent of all the types and accounts for more than two-thirds of all cases, while CMT2 is the next most common. These types are again divided into several subtypes, of which CMT type 1A is the commonest. In about 90% of cases, CMT disease is inherited in an autosomal dominant fashion, although autosomal recessive and X-linked inheritance may occur. It is also possible for CMT to develop as a result of a spontaneous mutation. In CMT1A, which is inherited in an autosomal dominant fashion, there is duplication of the peripheral myelin protein-22 (PMP22) gene on chromosome 17. This results in unstable myelin which spontaneously breaks down, leading to demyelination. The Schwann cells subsequently attempt to compensate for this by proliferating and remyelinating. The process of breakdown and remyelination occurs in repeated episodes, giving rise to an "onion bulb" appearance - i.e. multiple concentrically laminated Schwann cell processes separated by collagen fibers. The other types of CMT also give rise to demyelination, except CMT2, where there is progressive axonal loss. The characteristic clinical findings of CMT are slowly progressive symmetrical distal muscle weakness and atrophy, impaired sensation, and absent or hypoactive deep tendon reflexes. The age of presentation varies, but in most cases is within the first two decades of life. The weakness usually begins in the distal muscles of the lower extremities. Initial complaints include difficulty walking, frequent trips or falls (due to foot and distal leg weakness) and frequent ankle sprains. As the disease progresses, foot drop and a high stepping gait may develop. Many patients also develop structural deformities such as a high arched foot (pes cavus) and hammer toes. Distal muscle wasting in the legs gives rise to the characteristic appearance of an "inverted champagne bottle". The upper limbs are involved relatively late in the course of the disease. Wasting of the small muscles of the hand may result in impaired fine movements (such as writing or buttoning clothing). Patients with certain phenotypes of CMT disease may experience mild tingling and burning sensations, and may go on to develop severe neuropathic pain requiring analgesics. Complete sensory loss is uncommon, but may occur, leading to patients injuring themselves unknowingly. Rarely, sensory loss may lead to gradual hearing impairment and deafness. Other examination findings include scoliosis, thickened and palpable peripheral nerves, decreased vibratory sensation and proprioception, markedly diminished or absent deep tendon reflexes, sensory gait ataxia and a positive Romberg test. A tremor is present in some patients. Respiratory muscle weakness is a rare manifestation. The diagnosis of is based upon the symptoms, family history, neurological examination, electrodiagnostic tests, nerve biopsies and genetic studies. Electrodiagnostic tests are important in distinguishing the axonal from the demyelinating forms of the disorder. Demyelinating CMT shows a severely reduced motor nerve conduction velocity (< 38 m/s), while the axonal type shows a normal velocity, but reduced amplitude of compound muscle action potentials. Nerve biopsies show segmental demyelination and remyelination with onion bulb formation in CMT1; and loss of myelinated axons in CMT2. Genetic tests are available for certain subtypes of CMT disease, and are helpful for definitive diagnosis and genetic counselling. There is no known cure for CMT disease - treatment is aimed at improving the quality of life and function of the patient. A multidisciplinary team, including neurologists, orthopedic surgeons, podiatrists, physiotherapists and occupational therapists should be involved in the treatment. Physiotherapy, occupational therapy, braces and other orthopedic devices and orthopedic surgery can help these patients cope with the disabling symptoms of the disease. In addition, analgesics should be prescribed for individuals with severe pain. Patients should also be advised to avoid medications known to cause nerve damage (such as nitrofurantoin and isoniazid). The prognosis varies by subtype - but in most cases, life expectancy is normal. Nevertheless, regular follow up visits are needed to check for deterioration in function, development of contractures and early detection of complications. All affected patients (and in the case of children, their parents) should receive genetic counseling.