An Indian Family with Autosomal Recessive Charcot Marie Tooth Disease

Sir, Charcot Marie tooth (CMT) is a syndrome of several genetically distinct disorders. The various subtypes are classified according to the nerve conduction velocities and predominant pathology, inheritance pattern, and specific mutated gene.[1] The transmission of this disease occurs most frequently in the autosomal dominant (AD) mode; however, on rare occasions it can be autosomal recessive (AR) or X - linked recessive (XLR).[2] In most communities ARCMT is far less common than ADCMT. Here, we describe a family with 5 affected siblings out of a total of 10 born to unaffected parents, thus reflecting an autosomal recessive pattern of inheritance. AM, a 38-year-old male from West Bengal, India, presented with complaints of gradually progressive weakness and wasting of both lower limbs since 25 years. He is fourth child born of third degree consanguineous marriage. He achieved all developmental milestones on time. However at about 13 years of age he noticed difficulty in walking or running for long distances when compared to his peers. The weakness gradually progressed over the years. He gives history of tripping over uneven ground and difficulty in holding slippers in foot. There was no history of visual disturbances or hearing loss or incontinence or orthostatic light headedness. Examination revealed normal higher mental functions and cranial nerve functions, bilateral pes cavus, hammer toes, foot drop; symmetrical wasting of anterior tibial, peroneii [Figure 1], calf muscles, thenar, and hypothenar muscles with mild weakness (power– 4/5) and global areflexia [Figure 2]. The sensations of vibration and proprioception were impaired in both upper and lower limbs. Pain and temperature sensations were diminished below mid – calf levels bilaterally. Peripheral nerve palpation revealed bilaterally thickened peroneal nerves. There was no spinal deformity and no postural drop of blood pressure. Fundus examination was found to be normal.Figure 1: Siblings with peroneal muscle atrophyFigure 2: Hammer toes and pes cavusThe examination of his siblings, NK, a 32-year-old female; SF, a 30-year-old male and RK, a 26-year-old female revealed similar pattern of illness. The disability was however less in the youngest sibling. A detailed family history revealed that paternal and maternal grandmothers of the index case were cousins. The parents of the index case however do not complain of any similar illness nor do they give any history of similar complaints by their own siblings. A total of 5 out of 10 offsprings including the index case were affected. One of the affected offsprings had died at an age of 15 years due to an unrelated cause. Pedigree analysis revealed an autosomal recessive pattern of inheritance [Figure 3]. No individual in the generation subsequent to the index case was found to be affected.Figure 3: Pedigree chart of the family with ARCMTBasic hematological, biochemical, cerebrospinal fluid studies, and neuroimaging studies were normal. Nerve conduction studies revealed slowing of motor nerve conduction velocities in both upper limbs (range- 19--26 m/s) and lower limbs (24--31 m/s) with delayed latency and reduced compound muscle action potentials (CMAPs-0.2--3.3 mV). F wave study showed delayed response in tested nerves. Sensory nerve conduction velocities were also reduced in both upper limbs (28-35 m/s) and lower limbs (29- 35/s). The sensory nerve action potentials amplitudes were reduced (1--3 microvolt’s). Electromyography Studies were normal. Electrophysiological study (EPS) of one of the affected sisters was remarkably similar to that of the index case. EPS of both parents was however proved to be normal. A final diagnosis of AR form of CMT was made. A further genetic testing could not be performed. The index case and the affected siblings were provided supportive care. CMT disease is a clinically and genetically heterogeneous disorder. It is the commonest cause of peroneal muscular atrophy syndrome of distal leg muscle wasting and weakness, usually accompanied by pes cavus deformity. Occasionally CMT disease is associated with other neurological features, such as spastic paraparesis, optic atrophy, pigmentary retinal degeneration, deafness, the dysmorphic Noonan syndrome, or the mental retardation associated with agenesis of corpus callosum, also known as Andermann syndrome.[3] CMT disease can be classified into types 1--4 on clinical, electrophysiological, and genetic grounds.[3] A conduction velocity below 38 m/s in forearm segment of median nerve is proposed as a cut-off value to distinguish between CMT1 and CMT2.[3,4] Intermediate forms of CMT, with median or ulnar nerve motor conduction velocities between 25--45 m/s, are also present. In the hereditary motor sensory neuropathy (HMSN) classification, severely affected infants with the demyelinating form were classified as having HMSN III (also called congenital hypomyelinating neuropathy (CHN) or Dejerine--Sottas neuropathy (DSN)). This group of diseases was thought to be autosomal recessive (AR) but since many of these patients actually have de novo dominant (AD) mutations in the genes that commonly cause AD CMT1, we now use the terms CHN or DSN for this group and hence there is no CMT3.[5] CMT1 and vast majority of CMT2 subtypes display autosomal dominant inheritance.[4] But there are AR forms of both CMT1 and CMT2. AR forms of CMT1 are now called CMT4, whereas the much more rare AR forms of CMT2 are generally referred to as AR CMT2.[5] HMSN type V denotes associated pyramidal signs.[6] In HMSN type VI, optic atrophy is found in addition to peroneal muscular atrophy.[6] In total, 37 identified genes or loci have been identified so far as responsible for the different forms of CMT disease. Four gene abnormalities account for about two thirds of all patients with CMT disease. Over half of them have a reduplication of the gene for peripheral myelin protein 22, PMP22 which produces type 1 demyelinating form. A total of 5--10% carry X- linked Connexin- 32, Cx-32 mutations which variably produce type 2 axonal or milder degrees of type 1 demyelinating neuropathy. Another 5% are due to mutations of the myelin protein Po gene, MPZ, or the PMP22 gene producing mixture of type 1 demyelinating and type 2 axonal forms.[3] Because a great variability in clinical expression exists among affected kin in dominant disorders, a recessive inheritance can only be accepted if the clinical and electrophysiological examinations of both parents have proved to be normal.[4] The findings in our patient which suggested a Type 1 CMT phenotype are median nerve conduction velocity less than the cut off 38m/s (right-19.35 m/s, left-22.03 m/s), pes cavus deformity, palpable peroneal nerve thickening, a normal CSF protein level (34 mg/dl) and a slow rate of progression of symptoms. The autosomal recessive inheritance was sought because of absence of any clinical or neurological evidence of disease in the parents with occurrence of disorder in five out of ten siblings without any sex predilection. Since AR forms of CMT1 are now classified as CMT type 4, we report this case as CMT type 4. In most UK/North European and US populations, about 90% of cases of CMT are either AD or X-linked, whereas in countries with a higher rate of consanguineous marriages, AR CMT can account for up to 40%.[5,7] The exact prevalence of CMT in Indian population is unknown, with most of the documented cases having an AD transmission. However, a fair number of cases with AR inheritance have been identified in the gypsies of India, who are known to practice consanguinity.[2] It is important to identify such families so as to modify and address the sociocultural issues to prevent clinically manifest disease in subsequent generations. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.