Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe

Abstract

We describe a previously not recognized nonsense mutation in exon 10 of the ALS2 gene in two sibs with infantile-onset ascending spastic paralysis. The mutation predicts chain termination at amino-acid position 715 of the gene product ALSIN (p.Gln715X). The sibs' parents are descendants of a common ancestor who lived in the northern Netherlands during the eighteenth century. This is the first ALS2 mutation detected in northwestern Europeans. The findings emphasize that mutations in ALS2 also need to be considered in patients from northwestern Europe with early-onset spastic paralysis and amyotrophic or primary lateral sclerosis. In ALS2 both upper and lower motor neurons are affected, whereas neurodegeneration only involves upper motor neurons in JPLS and IAHSP. 5,6 Despite this difference in neuropathology, there is considerable clinical overlap of the major signs and symptoms in the three conditions, including spasticity of the limbs and dysarthria. The age of onset is during early childhood (first or second year), in the three disorders but appears to be somewhat later in ALS2 than in JPLS and IAHSP. The ALS2 gene is located on the long arm of chromosome 2 (2q33) and is composed of 34 exons.1,2 It can be transcribed into two alternative transcripts of 6.5 and 2.6 kb. The large transcript encodes ALSIN, a protein of 184 kD. ALSIN contains three putative guanine nucleotide exchange factor (GEF) domains, the N-terminal regulator of chromatin condensation (RCC1) domain, the central Db1 and pleckstrin homology (DH/PH) domains, and the C-terminal vacuolar protein sorting 9 (VPS9) domain. European Journal of Human Genetics (2008) 16, 1407-1411 & 2008 Macmillan Publishers Limited All rights reserved 1018-4813/08 $32.00 www.nature.com/ejhgIt is not known whether the short transcript is physiologically translated into a functional polypeptide as well.To date, a total of 12 different mutations have been described in the ALS2 gene. All had occurred in people from Mediterranean countries and from Asia. Here we describe the first mutation in ALS2 in sibs from northwestern Europe. They are the children of consanguineous parents, who are descendants of a common ancestor who lived in the eighteenth century (around 1750) in the province of Friesland, in the northern part of the Netherlands. The findings are discussed in the context of published ALS2 mutations. Materials and methodsDNA extraction and sequencing of the 34 exons of ALS2 were performed according to standard procedures. Case reportsPatient 1, the proband, is the first child of healthy parents of Dutch descent. She was born at term after an uncomplicated pregnancy and delivery. At the age of 8 months she developed distal spasticity in her legs and axial hypotonia. She was never able to sit or stand without support. During the following 3 years, spastic diplegia slowly progressed to the upper extremities. Starting at age 5, she developed tetraplegia; with the lower extremities being more severely affected than the upper extremities, soft pseudobulbar speech, and dysp...

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

“…At least 22 of the reported ALS2 pathogenic variants have been associated with IAHSP and have been described in a total of 42 individuals. The majority of reported cases originate from the Middle East and Mediterranean countries [2][3][4][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Table 2 provides a summary of the mutations and clinical features of the previously reported IAHSP cases.…”

“…Wheelchair dependence occurs in the second decade of life. Incontinence and feeding via a gastrostomy have been described in some individuals in the advanced stages of the disease [17]. Scoliosis, although reported, is uncommon.…”

Association of cerebral palsy with consanguineous parents and other risk factors in a Palestinian population

“…With 60% of cerebral palsy cases having an unknown cause other than suspected prepartum risk factors (25) means this area warrants attention, especially in countries with a large consanguineous population. Small-scale studies have identified nonsense mutations (26) and for consanguineous populations there may be genes which have temporal or site-specific targets that act on the developing brain. At present access to genetic diagnostic testing is limited.…”

Loss of ALS2/Alsin Exacerbates Motor Dysfunction in a SOD1H46R-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking

“…These disorders are characterized by ascending degeneration of UMN with or without LMN involvement. A total of 19 independent ALS2 mutations from 17 families have been reported [4], [5], [6], [10], [11], [12], [13], [14]. They are predicted to result in either premature termination of translation or substitution of an evolutionarily conserved amino acid for the ALS2 -coded protein, ALS2 or alsin, leading to loss of its function.…”