ALS2-Related Disorders via the ALS2 Gene

Amyotrophic lateral sclerosis (ALS, OMIM 105400) is a neurodegenerative disease characterized by selective loss and dysfunction of both upper motor neurons (UMN) of the motor cortex and lower motor neurons (LMN) of the brainstem and spinal cord (Tandan and Bradley Ann Neurol 18:271-280, 1985; Brooks J Neurol Sc 124(Sup):96-107, 1994). The dysfunction and loss of UMN result in spasticity in the legs leading to difficulty in walking, lack of movement coordination and brisk reflexes. Damage to LMN results in weakness, muscle wasting, and fasciculation. Symptoms usually begin with asymmetric involvement of the muscles. Juvenile ALS (ALSJ, OMIM 205100) is distinguished from classical ALS by its early onset and slow progression. In ALSJ, the age of onset varies between 3 and 10 years of age, and the mean disease duration ranges between 2 and 28 years (Ben Hamida et al. Brain 113(Pt 2):347-363, 1990). As is the case for classical ALS, ALSJ is clinically heterogeneous, and its phenotype is influenced by the relative ratio of UMN and LMN involvement (Yang et al. Nat Genet 29:160-165, 2001).

Infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM 607225) is a motor neuron disease characterized by a degeneration of the UMN of the corticospinal tract. The clinical hallmark of IAHSP is a slow, progressive, ascending spastic paralysis. Spasticity usually begins in the lower limbs, extending to the upper limbs and bulbar muscles and, eventually, to a severe spastic paralysis. The onset of symptoms typically occurs during the first two years of life, with most patients being wheelchair-bound by the age of ten. The disease progresses to tetraplegia (complete paralysis of both upper and lower limbs), anarthria (total or partial loss of articulate speech), dysphagia (difficulty in swallowing) and slow eye movements in the second decade of life. Despite the progressive nature of the disease, life expectancy is not affected (Eymard-Pierre et al. Am J Hum Genet 71:518-527, 2002; Lesca et al. Neurology 60:674-882, 2003).

Primary lateral sclerosis (PLS) is characterized by neurological dysfunction limited to the UMN of the corticospinal tract (Russo Arch Neurol 39:662-664, 1982). The most common features of PLS are spastic quadriparesis, hyperactive muscle-stretch reflexes, and bilateral Babinski's sign. Additional features include spastic dysarthria, dysphagia, and exaggerated affective responses such as weeping or loathing. PLS is typically characterized by a gradual onset, slow and steady progression, and long duration (Beal and Richardson Arch Neurol 38:630-633, 1981). Two forms of PLS, juvenile and adult, are recognized based on the age of onset. In juvenile PLS (JPLS, OMIM 606353) symptoms begin in early childhood, sometimes before twelve months of age (Grunnet et al. Neurology 39:1530-1532, 1989); in adult PLS (PLSA1, OMIM 611637) the age of onset varies between 35 and 66 years of age (Pringle et al. Brain 115 (Pt 2):495-520, 1992). JPLS is always inherited with an autosomal recessive manner, while adult PLS is either sporadic or autosomal dominant.

Juvenile amyotrophic lateral sclerosis (ALSJ) is most often inherited in an autosomal recessive pattern and has been generally reported in North African (Hentati et al. Nat Genet 7:425-428, 1994) and Middle Eastern populations (Kress et al. Ann Neurol 58:800-803, 2005). ALSJ is caused by variants in the ALS2 gene (Yang et al. Nat Genet 29:160-165, 2001; Hadano et al. Nat Genet 29:166-173, 2001; Kress et al. Ann Neurol 58:800-803, 2005; Bertini et al. GeneReviews, 2005). To date, three small homozygous deletions were reported in patients with ALSJ from consanguineous families. All deletions resulted in a predicted truncated protein with loss of function. In addition to ALSJ, variants in the ALS2 gene have been reported in patients with juvenile primary lateral sclerosis (PLSJ), infantile-onset ascending spastic paralysis (IAHSP), and complicated hereditary spastic paraplegia (cHSP, Gros-Louis et al. Ann Neurol 53:144-145, 2003).

IAHSP is transmitted in an autosomal recessive pattern and is genetically heterogeneous. Variants in the ALS2 gene cause IAHSP in a subset of patients (Eymard-Pierre et al. Am J Hum Genet 71:518-527, 2002). At least eight ALS2 variants have been reported in patients with IAHSP (Devon et al. Clin Genet 64:210-215, 2003; Verschuuren-Bemelmans et al. Eur J Hum Genet 16:1407-1411, 2008; Bertini et al. GeneReviews, 2005). Except in one compound heterozygote case (Sztriha et al. Clin Genet 73:591-593, 2008), all variants were homozygous and resulted in a predicted truncated protein. In some cases, parents were closely related, while a history of consanguinity was absent in others. These variants occurred in patients of North African and European origins.

JPLS is caused by variants in the ALS2 gene (Hadano et al. Nat Genet 29:166-173, 2001; Yang et al. Nat Genet 29:160-165, 2001; Bertini et al. GeneReviews, 2005). To date, four homozygous variants in the ALS2 gene were found in patients with JPLS. These include two 2 bp deletions in families from Saudi Arabia (1867delCT; Yang, 2001) and Kuwait (1425delAG; Hadano, 2001), a nonsense variant (c.1619 G>A) in an Italian family (Panzeri et al. Brain 129(Pt 7):1710-1719, 2006), and a splice site variant (c.2980-2A>G) in a Cypriot family (Mintchev et al. Neurology 72:28-32, 2009). While consanguinity was documented in the families from Saudi Arabia, Kuwait and Cyprus, the Italian family did not illustrate a history of consanguinity. Patients from all families showed the first symptoms before the age of two years. All four variants resulted in a predicted truncated protein with loss of function.

Currently unknown.

This test provides full coverage of all coding exons of the ALS2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).