Amyotrophy, Monomelic

Description

Monomelic amyotrophy, also known as Hirayama disease, is characterized by insidious onset of weakness and wasting of the muscles of the hand and forearm. It is usually unilateral, but can be bilateral. It occurs most commonly as a sporadic condition, is most common in young men, and follows a relatively benign course after a few years of progression (Nalini et al., 2004; Misra et al., 2005).

Clinical Features

Hirayama et al. (1959) first described juvenile muscular atrophy of an upper extremity in Japanese patients. Hirayama (1972) reported 38 patients with juvenile nonprogressive muscular atrophy confined to the hand and forearm.

Gucuyener et al. (1991) described a brother and sister, 6 and 8 years of age, respectively, with proximal muscle weakness confined to 1 arm. Electrophysiologic studies suggested localized chronic anterior horn cell disease. The authors suggested autosomal recessive inheritance in this family. In the girl, the weakness and atrophy began in the left arm at 4 years of age, 3 months after the injection of DTP vaccine into that arm; in the boy, onset of weakness and atrophy of the right arm occurred 1 year after injection of DTP into the same arm. The benign nature, unilateral atrophy confined to the muscles of 1 limb, and the restriction of the disease to a few cervicodorsal segments even after many years, distinguishes monomelic amyotrophy from progressive spinal muscular atrophy (see, e.g., SMA1, 253300). In 20% of patients with neuralgic amyotrophy (see 162100), previous immunization with tetanus toxoid had been recorded, but in that disorder the onset of symptoms is explosive with great pain; weakness begins after the pain subsides. Although there was a history of DTP vaccination in both patients, Gucuyener et al. (1991) pointed out that in their patients, the clinical course was not compatible with neuralgic amyotrophy. Delayed post-poliomyelitis syndrome, which begins many years after recovery from acute paralytic poliomyelitis, was considered unlikely because the patients had been vaccinated for polio and had no history of poliomyelitis during infancy, and also because of their young ages.

Nalini et al. (2004) reported an Indian mother and son with unilateral monomelic amyotrophy. The son presented at age 21 with a 3-year history of gradually progressive weakness and wasting of the small muscles of the left hand and forearm, manifest as an inability to perform fine work, like buttoning and gripping objects firmly. One year after disease onset, he developed fasciculations over the left arm and forearm followed by tremulousness of the hand and clawing. He also experienced exacerbation of motor weakness on exposure to cold. The illness reached a stationary phase after about a year. The patient's mother had onset of cold-induced paresis in the right hand at age 20 years, which progressed to weakness and wasting of the hand and forearm muscles 10 years later. Physical exam in both patients showed mild wasting and weakness of the affected hand and upper limb, with sparing of the brachioradial muscle. EMG in both patients suggested chronic denervation with reinnervation. Although MRI of the spinal cord was normal in the son, MRI in the mother showed signal changes at C4-C5.

Rigamonti et al. (2004) reported a sporadic case of Hirayama disease in a 20-year-old Italian man. MRI showed unilateral anterior spinal cord atrophy from C5 to C7. The authors noted that the condition may be caused by neck flexion-induced ischemic myelopathy confined to the lower cervical cord.

Misra et al. (2005) reported 15 male patients with Hirayama disease from 14 Indian families; 2 patients were brothers. Mean age at disease onset was 18 years (range, 15 to 23 years), and disease duration was approximately 6 months to 2 years. All patients had unilateral upper limb weakness, which became bilateral in 8 patients. Six patients had cold paresis. EMG showed fibrillations in 10 patients, fasciculations in all patients, and neurogenic changes restricted to the C7, C8, and T1 myotomes in all patients. Nerve conduction velocities of the median and ulnar nerves were normal in 13 patients. Median spinal MRI showed cervical cord atrophy in 7 of 11 patients; 3 patients had a normal MRI.

Jeannet et al. (2005) reported a 10-year-old girl with Hirayama disease affecting the left hand and forearm. Cervical MRI was normal. Since infancy, the patient had exhibited a rhythmic movement disorder during sleep in which she rocked back and forth, flexing her neck violently and repeatedly. On the advice of the authors, the parents awakened the patient at the start of body rocking, and the behavior disappeared within 2 weeks and did not recur. At 3-year follow-up, she had no progression of symptoms in her hand and forearm. Jeannet et al. (2005) noted that the onset of symptoms of Hirayama disease in this girl corresponded to the onset of the adolescent growth spurt. They postulated that disproportionate shortening of the dorsal roots combined with severe repeated neck flexion contributed to the symptoms.

Pathologic Findings

Hirayama et al. (1987) reported the neuropathologic findings in a patient with a 23-year history of Hirayama disease. Anterior horn cells of spinal cord levels C5-T1 showed shrinkage, degeneration, and necrosis with mild gliosis. The changes were particularly marked at C7 and C8. The authors suggested circulatory insufficiency in these areas.

Inheritance

Gucuyener et al. (1991) stated that monomelic amyotrophy most often occurs sporadically; however, Hirayama (1972) and Sobue et al. (1978) reported familial cases. The family of Sobue et al. (1978) had affected father and son. Schlegel et al. (1987) reported a Caucasian man and son with focal muscular atrophy of the upper limb, suggesting autosomal dominant inheritance. Both father and son had onset at age 16 years.

Tandan et al. (1990) reported identical male twins with chronic segmental spinal muscular atrophy confined to the upper extremities, suggesting a genetic etiology in a subset of cases. Age at onset was 16 and 17 years, respectively.

Nalini et al. (2004) stated that there had been 5 reports of familial monomelic amyotrophy reported in the English literature: 5 families suggested autosomal recessive inheritance and 2 suggested autosomal dominant inheritance. Of 190 cases seen over 27 years, Nalini et al. (2004) identified only 1 instance of a familial case in a mother and son.

Molecular Genetics

Associations Pending Confirmation

By whole-exome sequencing of 4 unrelated Korean boys with monomelic amyotrophy, followed by selective genotyping of candidate variants in 24 patients, Lim et al. (2012) found a significant association between the disorder and 2 SNPs in 2 different genes compared to controls: a gly668-to-ser (G668S; rs76022391) variant in the KIAA1377 gene (614634) on chromosome 11q22 (odds ratio (OR) of 4.62, p = 0.0040), and a pro1794-to-leu (P1794L; rs75589774) variant in the C5ORF42 gene (614571) on chromosome 5p13 (OR of 4.63, p = 0.0040). Four of the patients with the G668S variant carried it on the same haplotype, suggesting a common origin. However, only 1 copy of the causal variant in either gene did not affect risk for the development of the disorder: significant association for the disorder was only found with a combination of heterozygosity for both variants (OR of 61.99, p = 1.4 x 10(-5)) or with homozygosity for the KIAA1377 variant (OR of 41). The data suggested that KIAA1377 and C5ORF42 may synergistically play a role as susceptibility genes for monomelic amyotrophy.

Exclusion Studies

Di Guglielmo et al. (1996) excluded deletions in the SMN1 (600354) and SMN2 (601627) genes in 7 patients with monomelic amyotrophy.

Misra et al. (2005) excluded deletions in the SMN1 and SMN2 genes in 15 males with Hirayama disease. They noted a preponderance of males with the condition and suggested a role for the X chromosome.