Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Our data denote a rather variable course of neuromuscular deficits in chronic adult-onset Pompe patients during 36 months of alglucosidase alfa ERT.

BackgroundPain is an often underestimated and neglected symptom in amyotrophic lateral sclerosis (ALS).MethodsIn a cross-sectional survey, 46 patients with ALS, 46 age- and gender matched population-based controls, and 23 diseased controls with myotonic dystrophy type 2 (DM2) were screened for occurrence, type, distribution, and treatment of pain and cramps. Data were collected with the use of the short form brief pain inventory (BPI).ResultsPain was reported in 78% of ALS patients,79% of DM2 patients, and 54% of controls (P < 0.05). More ALS patients than controls reported moderate to severe pain (42% vs. 20%). Pain in ALS patients interfered significantly more with daily activities than in controls (median pain interference score: 3.0 vs. 1.2, P < 0.05), especially enjoyment of life (5.0 vs. 1.0) and mood (3.0 vs. 1.0). There was no correlation between the duration of the disease and the severity of pain. Movement-induced cramps were reported in 63% of ALS patients, mostly in the distal extremities. There was no difference in the duration of ALS disease between patients reporting cramps and those who did not.DiscussionOur study showed that pain was a relatively frequent symptom which had an important impact on the quality of life. Pain that requires treatment can occur at every stage of ALS.

Intronic hexanucleotide (G 4 C 2 ) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat-dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G 4 C 2 repeat RNA. We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci.