Recessive Ataxia With Ocular Apraxia

Abstract

Ataxia with ocular apraxia may be more frequent than postulated before, and may be identified clinically using the following criteria: (1) autosomal recessive transmission; (2) early onset (for most patients in early childhood); (3) combination of cerebellar ataxia, ocular apraxia, and early areflexia, with later appearance of the full picture of peripheral neuropathy; (4) absence of mental retardation, telangiectasia, and immunodeficiency; and (5) the possibility of a long survival, although with severe motor handicap.

Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4

“…Chromosomal instability, immunodeficiency, and sensitivity to ionizing radiations, all usually observed in persons with ataxia telangiectasia (AT) and AT-like disorders, are absent in individuals with AOA. 1 Early-onset recessive ataxia (AOA1 or EAOH [MIM 208920 ]) is a progressive syndrome associated with hypoalbuminemia and elevated levels of cholesterol and is caused by mutations in APTX (aprataxin). 1–3 Autosomal-recessive spinocerebellar ataxia 1 (AOA2 or SCAR1 [MIM 606002 ]), a progressive ataxia, 4 occurring later than AOA1, is characterized by increased alpha-fetoprotein levels and is caused by mutations in SETX (senataxin).…”

Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease

“…Both diseases have early onset, with AOA4 being the earliest (mean age onset 4.3 vs. 6.9 years for AOA1). Extra-neurologic features are also similar as half of the AOA4 cases have low albumin and high cholesterol, features found consistently in older AOA1 patients (Barbot et al, 2001; Bras et al, 2015; Moreira et al, 2001; Yokoseki et al, 2011). A clinically related syndrome AOA2, is caused by mutations in Senataxin (Anheim et al, 2009; Hammer et al, 2012; Le Ber et al, 2004; Moreira et al, 2004), a helicase, which is associated with DNA damage responses, transcriptional control and possibly a SSBR defect (Bennett and La Spada, 2015; Hamperl and Cimprich, 2014; Richard et al, 2013; Suraweera et al, 2007).…”

“…These syndromes impact cerebellar function and result in a profound loss of motor control and are characterized by cerebellar degeneration, oculomotor apraxia (abnormal saccadic eye movement) and often dystonia and peripheral neuropathy (Anheim et al, 2012; Barbot et al, 2001). AOA4 is an autosomal recessive ataxia recently identified in 11 Portuguese patients (from 8 different families), caused by PNKP mutation and represents the most common AOA in Portugal (Bras et al, 2015).…”

Autosomal recessive cerebellar ataxias

“…The disease has been originally reported in Portuguese [61] and Japanese [62] patients. In Japan, AOA1 seems to be the most frequent recessive ataxia, whereas in Portugal it is the second one, after Friedreich ataxia [63].…”