Amyotrophic Lateral Sclerosis 21
A number sign (#) is used with this entry because amyotrophic lateral sclerosis-21 (ALS21) is caused by heterozygous mutation in the matrin-3 gene (MATR3; 164015) on chromosome 5q31.
DescriptionAmyotrophic lateral sclerosis-21 is an autosomal dominant neurodegenerative disorder affecting upper and lower motor neurons, resulting in muscle weakness and respiratory failure. Some patients may develop myopathic features or dementia (summary by Johnson et al., 2014).
For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Clinical FeaturesFeit et al. (1998) described a large American family segregating an autosomal dominant distal myopathy, with multiple affected individuals in whom vocal cord and pharyngeal weakness may accompany the distal myopathy, without involvement of the ocular muscles. From a histopathologic standpoint, the lesion observed in these individuals was a noninflammatory myopathy with rimmed vacuoles probably fitting into the spectrum of the inclusion-bodied myopathies. Overall, the myopathy was mild or moderate. They stated that this 'form of distal myopathy has not been previously recognized and is distinct from other myopathies with pharyngeal or vocal weakness.' They referred to the clinical disorder as VCPDM (vocal cord and pharyngeal dysfunction with distal myopathy). Senderek et al. (2009) expanded the family described by Feit et al. (1998) with 2 additional sibs from an additional branch of the family. They also described a multigenerational Bulgarian family with a typical VCPDM phenotype. Upon reexamination of the family originally reported by Feit et al. (1998), Johnson et al. (2014) found that affected individuals developed progressive respiratory failure resulting in death about 15 years after symptom onset. Four of 6 patients examined showed hyperreflexia of the lower limbs, indicative of upper motor neuron involvement. One patient also had hyperreflexia of the upper limbs, tongue fasciculations, and a brisk jaw jerk. All patients had a 'split-hand' pattern of weakness, suggestive of a lesion in the anterior horn of the spinal cord. These clinical findings led Johnson et al. (2014) to reclassify the disorder in this family as a form of slowly progressive amyotrophic lateral sclerosis rather than a myopathy. Many of the patients in this family also had significant distal sensory impairment of the lower limbs.
Johnson et al. (2014) reported a large family of European origin segregating ALS and dementia in an autosomal dominant pattern of inheritance. Clinical details of 5 patients were provided, although family history suggested that other deceased family members had been affected. The age at onset ranged from the early fifties to the seventies and was characterized by distal muscle weakness and cramping of the upper or lower limbs, and bulbar signs, such as dysarthria and dysphagia. All patients developed progressive upper and lower motor neuron signs affecting all 4 limbs, and at least 3 patients died of respiratory failure. Most patients also had cognitive impairment or dementia. Two affected individuals from an unrelated Sardinian family had onset of distal muscle weakness at ages 60 and 62 years, respectively. Imaging of 1 patient showed bilateral corticospinal tract damage. The other patient developed upper motor neuron signs and died of respiratory failure 33 months after onset. In a third family, an Indian man developed upper limb weakness at age 59 years. The symptoms spread to the lower limbs and bulbar muscles over the following 3 years, and he eventually became confined to a wheelchair and required ventilatory support, a gastrostomy tube, and an eye-tracking system for communication.
Muller et al. (2014) reported 16 patients from 6 unrelated German families with the S85C MATR3 mutation (164015.0001); haplotype analysis indicated a founder effect. The mean age at onset was 42.2 years (range, 30-55 years). Twelve patients presented with stumbling when walking uphill or climbing stairs due to weakness of the ankle dorsiflexors; 4 had difficulties rising from a squat due to muscle weakness of the proximal lower limbs; 2 had myalgia; and 2 had impaired hand function. Muscle weakness, which predominantly affected the distal lower limbs and the hands and fingers, was sometimes associated with muscle atrophy. Proximal muscle, neck muscle, and axial muscle weakness occurred in some patients, but was not common and tended to occur later in the disease course. Spasticity, hyperreflexia, and extensor plantar responses were not found, and tongue atrophy or fasciculations were not observed. Six patients had a nasal voice and 1 had a hoarse voice, but there was no evidence of vocal cord palsy. Six patients reported dysphagia of solid foods. Respiratory vital capacity was slightly decreased in 9 patients, and 3 needed assisted ventilation or oxygen therapy. Ten patients had increased serum creatine kinase, and EMG showed reduced amplitude and shortened duration of the motor unit potential. Muscle MRI showed fatty replacement of the thighs and lower legs, and muscle biopsies showed variable myopathic changes, including variation in fiber size, internal nuclei, and fatty replacement. Immunostaining showed MATR3 reactivity within muscle nuclei, but electron microscopy showed abnormal invaginations of the nucleus, perinuclear absence of sarcomeres, and presence of vacuoles. Muller et al. (2014) emphasized the lack of symptoms of motor neuron disease in these patients and suggested that the phenotype was more consistent with a distal myopathy than with ALS.
InheritanceThe transmission pattern of ALS21 in the families reported by Johnson et al. (2014) was consistent with autosomal dominant inheritance.
MappingBy use of combined genome screening and DNA pooling adapted to fluorescent markers, Feit et al. (1998) mapped the gene for the disorder, which they designated MPD2, to 5q, within a 12-cM interval between markers D5S458 and D5S1972 in this large pedigree (maximum lod score = 12.94 at a recombination fraction of 0.0 for D5S393).
In the family originally described by Feit et al. (1998), Senderek et al. (2009) reduced the candidate interval to a 5.37-Mb region on chromosome 5q31, between short tandem repeat (STR) markers sara2AC and AC008667C.
Molecular GeneticsIn the family described by Feit et al. (1998) and in an unrelated Bulgarian family with vocal cord and pharyngeal weakness with distal myopathy, Senderek et al. (2009) identified the same heterozygous missense mutation in the MATR3 gene (S85C; 164015.0001), which encodes a component of the nuclear matrix. Johnson et al. (2014) reclassified the disorder in the family reported by Feit et al. (1998) as ALS.
In affected members of a family of European ancestry with ALS21, Johnson et al. (2014) identified a heterozygous missense mutation in the MATR3 gene (F115C; 164015.0002). The mutation was found by exome sequencing. Most affected individuals in this family also had cognitive impairment or dementia. Exome sequence data from 108 additional familial ALS cases identified 1 heterozygous MATR3 missense mutation (T622A; 164015.0003) in an affected family. In addition, custom resequencing of genes linked to neurodegeneration in 96 British ALS cases identified a heterozygous mutation (P154S; 164015.0004) in a patient with sporadic disease. Immunohistochemical analysis of spinal cord section from a patient with the F115C mutation showed intense MATR3 immunoreactivity in the nucleus of all motor neurons and diffuse cytoplasmic staining in many neurons. Cytoplasmic inclusions were not present. Similar studies of spinal cord section from a patient with FTDALS (105550) due to the C9ORF72 repeat expansion (614260.0001) showed rare MATR3-positive cytoplasmic inclusions. MATR3 was also observed in the nuclei of remaining motor neurons and occasionally in the cytoplasm of spinal cord sections from non-MATR3 ALS. The findings suggested a role for aberrant RNA processing in motor neuron degeneration.
NomenclatureFeit et al. (1998) adopted the gene symbol MPD2 following the precedent of Laing et al. (1995), who had designated a form of distal myopathy that maps to 14q as MPD1 (160500). However, the disorder in the family reported by Feit et al. (1998) was later reclassified as amyotrophic lateral sclerosis by Johnson et al. (2014).