Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.

Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

Elevated satellite cell number in Duchenne muscular dystrophy.

The regenerative potential of muscle tissue relies mostly on satellite cells situated between the muscular basal membrane and the sarcolemma. The regeneration of muscle tissue comprises proliferation, the propagation of satellite cells, and their subsequent differentiation with the expression of multiple muscle-specific proteins. However, in Duchenne muscular dystrophy (DMD), regeneration cannot compensate for the loss of muscle tissue. To examine the regenerative potential in DMD, satellite cell nuclei number and markers of differentiation in DMD muscle from various disease states were compared with control muscle. Differentiation of satellite cells is characterized by the helix-loop-helix factor myogenin, which is never co-expressed with Pax7, whereas MyoD1 and Myf5 are co-expressed with Pax7, with Myf5 being present even in muscle of controls. The results indicate that satellite cell number is elevated in DMD in comparison with control muscle, even in advanced stages of dystrophy, suggesting that exhaustion of satellite cells is not the primary cause for failed regeneration. The expression of myogenin is correlated neither with fibrosis nor with age. We suggest variable factors influencing the differentiation of satellite cells in DMD.

Facioscapulohumeral muscular dystrophy presenting with isolated axial myopathy and bent spine syndrome.

Several subtypes of facioscapulohumeral muscular dystrophy (FSHD) with atypical clinical presentation have been described. We report a new, distinct phenotype with progressive bent spine syndrome solely affecting the paraspinal muscles. Magnetic resonance imaging study of the lumbar spine revealed marked atrophy of the paraspinal muscles. The diagnosis was confirmed by DNA testing, which revealed shortened restriction fragments of the D4Z4 repeat on haplotype A in connection with a positive family history.

Polysegmental innervation of the medial paraspinal lumbar muscles.

A retrospective analysis was performed in a nine month period of the electrophysiological data, imaging and clinical findings of patients with monoradicular disc herniation compressing either the L5 or the S1 nerve root. The primary purpose of the analysis was to determine the distribution of pathological spontaneous activity in the medial paraspinal muscles on electromyographic examination in monoradicular L5 and S1 nerve root compression syndromes. Anatomically, the medial paraspinal muscles receive their innervation from a single root while the iliocostalis muscles and the longissimus muscle are thought to be innervated by multiple nerve roots. In the analysis, in single nerve root lesion of the L5 or S1 nerve root, electromyography of the medial paraspinal muscles revealed pathological spontaneous activity one to three vertebrae cranial to the disc herniation with extension to the opposite side of the lesion. In conclusion, the medial paraspinal muscles might be thought to be innervated by one single nerve root on anatomical studies, electrophysiologically the extension of axonal lesion signs of one single lumbar nerve root is much broader. The widespread distribution of the L5 and S1 nerve root must be taken into consideration on electromyographic examination of the medial paraspinal muscles.

Dermatomyotomal supply in patients with variations in the number of lumbar vertebrae.

OBJECT: Variation in the number of lumbar vertebrae occurs in a small portion of the population. Either the fifth lumbar vertebra shows assimilation to the sacrum or the first sacral vertebra shows a lumbar configuration, resulting in 4 or 6 lumbar vertebrae, respectively. Etiologically, lumbar nerve root syndrome is diagnosed by comparing the anatomical level of the disc herniation to the compressed nerve root and to the pattern of the peripheral sensory and motor deficit. In case of a variation in the number of lumbar vertebrae, defining the lumbar nerve roots becomes difficult. Variations in the number of lumbar vertebrae make the landmarks (the twelfth rib and the first sacral vertebra) unreliable clues to define the nerve roots. The allocation of the clinically damaged segment to the spinal disorder seen in imaging studies is essential for differential diagnosis and spine surgery. METHODS: A retrospective study was conducted of clinical, electrophysiological, and imaging data among inpatients over a period of 21 months. Eight patients who had isolated monosegmental discogenic nerve root compression and a variation in the number of lumbar vertebrae were selected. RESULTS: Seven patients presented with 6 lumbar vertebrae, and 1 patient presented with 4 lumbar vertebrae and disc herniation on 1 of the 2 caudal levels. Compression of the second-to-last nerve root in patients with 6 lumbar vertebrae resulted either in clinical L-5 or S-1 syndrome, or a combination of both. Compression of the last caudal nerve root resulted in a clinical S-1 nerve root syndrome. CONCLUSIONS: The findings suggest that the dermatomyotomal supply of the lumbosacral nerve roots can vary in patients with a variation in the number of lumbar vertebrae, and a meticulous clinical, radiological, and electrophysiological examination is essential.

Late-onset autosomal dominant limb girdle muscular dystrophy and Paget's disease of bone unlinked to the VCP gene locus.

The broadwide spectrum of differential diagnoses of autosomal dominant muscular dystrophies in adults can be specified by additional features. The combination of late-onset muscular dystrophy, rimmed vacuoles and inclusion bodies in the muscle biopsy, and Paget's disease of bone suggests a mutation in the Valosin-containing protein gene (VCP, p97 or CDC48) even without dementia. We report on a German family with late-onset autosomal dominant muscular dystrophy starting in the pelvic girdle about age 40years, a subsequent rapidly-progressing course, high alkaline phosphatase and Paget's disease of bone. Clinical examination revealed no cognitive impairment. Histology showed myopathic changes with rimmed vacuoles and inclusion bodies on muscle biopsy. Mutations in VCP, filamin C, desmin, alphaB-crystallin, ZASP and myosin heavy chains 2 and 7 as well as the genes for facioscapulohumeral muscular dystrophy, Myotonic Dystrophy I and II, and LGMD1A-G were excluded by a combination of linkage analysis and direct sequencing. The family presented here suggests that a yet-unknown genetic defect can give rise to an autosomal dominant myopathy with Paget's disease but without dementia.

Muscle hypertrophy of the lower leg caused by L5 radiculopathy.

We report on a case with hypertrophy of the tibial muscles and to a lesser extent of the calf muscles preceded by a lumbar syndrome and sciatica. Lumbar myelography disclosed a discogenic compression of the L5 nerve root. Muscle biopsy of the peroneal muscles showed a marked type I fibre predominance and hypertrophy but no inflammatory infiltration. We consider the possibility that radiculopathy not only of the S1 nerve root but also of the L5 root can trigger hypertrophy of the musculature and must be taken into account of the differential diagnosis of unilateral focal hypertrophy of the lower leg.