Ataxia, Early-Onset, With Oculomotor Apraxia And Hypoalbuminemia
A number sign (#) is used with this entry because early-onset ataxia with oculomotor apraxia and hypoalbuminemia (EAOH) is caused by homozygous or compound heterozygous mutation in the gene encoding aprataxin (APTX; 606350) on chromosome 9p21. Adult-onset ataxia with oculomotor apraxia is also caused by mutation in the APTX gene.
DescriptionAtaxia-oculomotor apraxia syndrome is an early-onset autosomal recessive cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia (Moreira et al., 2001).
Genetic Heterogeneity of Ataxia-Oculomotor Apraxia
See also AOA2 (606002), caused by mutation in the SETX gene (608465) on chromosome 9q34; AOA3 (615217), caused by mutation in the PIK3R5 gene (611317) on chromosome 17p; and AOA4 (616267), caused by mutation in the PNKP gene (605610) on chromosome 19q13.
Clinical FeaturesAicardi et al. (1988) described an autosomal recessive syndrome that closely resembled ataxia-telangiectasia (AT; 208900) but differed in important respects. They reported 14 patients in 10 families with a neurologic syndrome of oculomotor apraxia, ataxia, and choreoathetosis who had none of the extraneurologic features of AT. Although the neurologic signs were indistinguishable from those of AT, the onset tended to be later and none of the patients had a tendency to frequent infections; further, immunoglobulins, alpha-fetoprotein, T- and B-lymphocyte markers, and chromosomes 7 and 14 were normal in all patients tested.
Barbot et al. (2001) reported 22 Portuguese patients with autosomal recessive cerebellar ataxia, ocular apraxia, and peripheral neuropathy with a mean age of onset of 4.7 years. There was no associated mental retardation, telangiectasia, or immunodeficiency. Barbot et al. (2001) concluded that ataxia with oculomotor apraxia may be more frequent than previously believed. Koeppen (2002) suggested that the patients reported by Barbot et al. (2001) may have exhibited supranuclear pseudoophthalmoplegia, which may be due to lesions in the nucleus pontis centralis caudalis of the paramedian pontine reticular formation.
Shimazaki et al. (2002) reported 5 Japanese patients with autosomal recessive EAOH from 3 families and 1 sporadic case. Clinical features included age of onset from 3 to 12 years, cerebellar ataxia, peripheral neuropathy, oculomotor apraxia and external ophthalmoplegia, choreiform movements of the limbs, facial grimacing, mental deterioration, cerebellar atrophy, hypoalbuminemia, and hypercholesterolemia.
Amouri et al. (2004) reported 3 unrelated Tunisian families with AOA, confirmed by mutation in the APTX gene (606350.0007; 606350.0008). The mean age at onset was 5 years with gait ataxia as the presenting symptom. Cerebellar ataxia affecting all 4 limbs and the trunk developed soon thereafter. Other features included dysarthria, ocular apraxia, distal sensory axonal neuropathy, and marked cerebellar atrophy by brain imaging. Hypoalbuminemia and hypercholesterolemia were also present. Affected members of 1 of the families had a somewhat atypical phenotype with absence of oculomotor apraxia, except in 1 patient, and preservation of knee reflexes. None of the patients had mental impairment.
Criscuolo et al. (2004) reported 3 unrelated Italian patients with AOA confirmed by genetic analysis. Two of the patients had adult onset at ages 28 and 29, respectively.
Criscuolo et al. (2005) reported a patient with adult-onset AOA confirmed by genetic analysis (606350.0009). The patient had onset of gait ataxia and dysarthria at age 40 years. Physical examination showed normal ocular movements, tongue and limb fasciculations, areflexia, and decreased vibration sense at the external malleoli. MRI showed cerebellar atrophy. Serum albumin was normal. Criscuolo et al. (2005) emphasized that milder phenotypes of AOA may occur in adults.
Castellotti et al. (2011) identified APTX mutations in 13 (6.4%) of 204 Italian patients with progressive cerebellar ataxia. The patients had onset between ages 3 and 7 years, but most were examined as adults. The phenotype was homogeneous, characterized mainly by gait and limb ataxia, dysarthria, nystagmus, lower limb areflexia, sensory neuropathy, cognitive decline, dysarthria, and oculomotor deficits. Some had choreic movements of the upper limbs and face, and many had distal muscle weakness and atrophy affecting both upper and lower limbs. Six patients were wheelchair-bound in young adulthood. Six patients had mental retardation since early childhood, whereas 5 showed cognitive decline later in life. Hypoalbuminemia was found in 58%, and hypercholesterolemia in 69%. Three patients had increased alpha-fetoprotein (AFP; 104150). Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in 5 of 6 patients. There were no genotype/phenotype correlations.
Biochemical FeaturesHannan et al. (1994) studied cultured fibroblasts from 3 patients with ataxia-oculomotor apraxia and their asymptomatic relatives in comparison with fibroblasts from a classic AT homozygote, an AT heterozygote, and 4 healthy subjects. Cell survival after acute and chronic irradiation was investigated. While a moderately increased cellular sensitivity (compared to normal) was observed in 2 AOA patients and most of their relatives, the degree of their radiosensitivity was quite different from that of the AT homozygote after both acute and chronic irradiation. A comparison of peripheral blood lymphocytes from spontaneous and acute radiation-induced chromosomal breaks also failed to show similarity between AOA and AT. The data were interpreted as indicating either that AOA and AT are distinct disease entities controlled by separate genes or that AOA is due to compound heterozygosity involving different AT genes that promote the manifestation of AOA characteristics.
PathogenesisAprataxin has been shown to interact with poly(ADP-ribose) polymerase-1 (PARP1; 173870), a key player in the detection of DNA single-strand breaks. Harris et al. (2009) reported reduced expression of PARP1, apurinic endonuclease-1 (APEX1; 107748) and OGG1 (601982) in AOA1 cells and demonstrated a requirement for PARP1 in the recruitment of aprataxin to sites of DNA single-strand breaks. Mouse embryonic fibroblasts (MEFs) derived from Parp1-knockout mice showed reduced levels of aprataxin and reduced DNA-adenylate hydrolysis; however, inhibition of PARP1 activity did not affect aprataxin activity in vitro. Rather, aprataxin failed to relocalize to sites of DNA single-strand breaks in Parp1-null MEFs compared to wildtype cells, and inhibition of PARP1 activity resulted in delayed recruitment of aprataxin to DNA breaks. There were elevated levels of oxidative DNA damage in AOA1 cells coupled with reduced base excision and gap filling repair efficiencies indicative of a synergy between aprataxin, PARP1, APE1 and OGG1 in the DNA damage response. Harris et al. (2009) proposed both direct and indirect modulating functions for aprataxin on base excision repair.
Garcia-Diaz et al. (2015) found that most, but not all, cell lines derived from AOA1 patient fibroblasts showed coenzyme Q10 (CoQ10) deficiency due to reduced mRNA and protein expression of PDSS1 (607429), the first committed enzyme of CoQ10 biosynthesis. Low PDSS1 was caused by reduced activity of a transcriptional regulatory pathway that included APE1, NRF1 (600879), and NRF2 (see 600609). Knockdown of APTX or APE1 in HeLa cells recapitulated CoQ10 deficiency and other mitochondrial abnormalities, and these abnormalities were reversed by upregulation of NRF2. Garcia-Diaz et al. (2015) concluded that mitochondrial dysfunction in APTX-depleted cells is not due to involvement of APTX in mtDNA repair, but rather to a role for APTX in transcriptional regulation of mitochondrial function.
Mapping9p Locus (APTX gene)
Date et al. (2001) identified a group of Japanese patients whose clinical presentation was characterized by autosomal recessive inheritance, early age at onset, Friedreich ataxia (FRDA; 229300)-like clinical presentations, and hypoalbuminemia. Linkage to the FRDA locus was excluded. They confirmed that the disorder in these patients was linked to the same locus, 9p13, as the ataxia-oculomotor apraxia syndrome.
Moreira et al. (2001) studied 13 Portuguese families with AOA and found that the 2 largest families showed linkage to 9p, with lod scores of 4.13 and 3.82, respectively, at a recombination fraction of 0.0. These and 3 smaller families, all from northern Portugal, showed homozygosity and haplotype sharing over a 2-cM region on 9p13.3, demonstrating founder effect and linkage to this locus, designated AOA1, in the 5 families. Three other families were excluded from this locus, demonstrating nonallelic heterogeneity in AOA. They also analyzed 2 unrelated Japanese families with early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA). This disorder, described only in Japan (Uekawa et al., 1992; Fukuhara et al., 1995; Sekijima et al., 1998; Tachi et al., 2000), is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and occasionally oculomotor apraxia. Both families appeared to show linkage to the AOA1 locus. Subsequently, the authors found hypoalbuminemia in all 5 Portuguese families with AOA1 with a long disease duration, suggesting that AOA1 and EOCA-HA correspond to the same entity that accounts for a significant proportion of all recessive ataxias.
9q Locus
Nemeth et al. (2000) identified a family with ataxia and oculomotor apraxia in which the disorder showed linkage to 9q34; see 606002. Bomont et al. (2000) performed linkage studies in the Japanese family reported by Watanabe et al. (1998) in which 4 affected sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, gamma-globulin, and alpha-fetoprotein. Homozygosity over a 20-cM region allowed demonstration of linkage at 9q33.3-q34.3 with a lod score of 3.0.
Koenig (2001) concluded that there are 2 recessive ataxia loci on chromosome 9: one on 9p, the site of the APTX gene, and one on 9q. The disorder that maps to 9p13 appears always to be associated with oculomotor apraxia (Barbot et al., 2001), early onset (usually between 2 and 6 years of age), and hypoalbuminemia after a long disease duration. The disorder on 9q34 is of later onset (between 11 and 22 years) and is occasionally associated with oculomotor apraxia or elevated gamma-globulin, alpha-fetoprotein, and creatine kinase. Tentatively, early-onset ataxia with oculomotor apraxia and hypoalbuminemia, which appears to map to 9p13.3 and to be caused by mutation in the aprataxin gene, will be referred to as ataxia-oculomotor apraxia-1, whereas ataxia of later onset with inconsistent association of oculomotor apraxia will be designated ataxia-oculomotor apraxia-2. Koenig (2001) suggested that the designation AOA is inappropriate for the form of ataxia mapped to 9q.
Population GeneticsBy 2001, the ongoing survey initiated in 1993 of hereditary ataxias and spastic paraplegias in Portugal, a country of 9.8 million persons, had identified 107 patients with autosomal recessive ataxia (Barbot et al., 2001). Friedreich ataxia (FRDA; 229300) accounted for 38% of the cases. The next most common recessive ataxia in the survey, accounting for 21% of the cases, was ataxia with oculomotor apraxia.
Anheim et al. (2010) found that AOA1 was the fourth most common form of autosomal recessive cerebellar ataxia in a cohort of 102 patients from Alsace, France. Of 57 patients for whom a molecular diagnosis could be determined, 3 were affected with AOA1. FRDA was the most common diagnosis, found in 36 of 57 patients, AOA2 (606002) was the second most common diagnosis, found in 7 patients, and ataxia-telangiectasia (AT; 208900) was the third most common diagnosis, found in 4 patients. Marinesco-Sjogren syndrome (MSS; 248800) was also found in 3 patients.
Molecular GeneticsDate et al. (2001) characterized 7 families from various regions of Japan with clinical manifestations like those of the ataxia-oculomotor apraxia syndrome and again showed mapping to 9p13 as in Europeans and people of European descent. They narrowed the candidate region and identified a novel gene encoding a member of the histidine triad (HIT, e.g., 601153, 601314) superfamily as the causative gene. They called its product aprataxin and assigned the gene symbol APTX (606350); this was the first member of the HIT superfamily to be linked to a distinct phenotype.
Moreira et al. (2001) and Date et al. (2001) demonstrated mutations in the APTX gene as the cause of AOA in their Portuguese and Japanese populations (606350.0001-606350.0004).
Castellotti et al. (2011) identified recessive APTX mutations in 13 (6.4%) of 204 Italian probands with progressive cerebellar ataxia. The most common mutation was W279X (606350.0006), which was found in homozygous state in 7 patients and in compound heterozygosity with another pathogenic APTX mutation in 1 patient. Three additional novel mutations were identified. Western blot analysis of patient lymphocytes showed severely decreased levels of APTX protein, consistent with loss of function as a disease mechanism. There were no genotype/phenotype correlations.
Genotype/Phenotype CorrelationsQuinzii et al. (2005) found that 3 sibs originally reported by Musumeci et al. (2001) as having familial cerebellar ataxia with muscle coenzyme Q10 (CoQ10) deficiency (see, e.g., COQ10D1, 607426) actually had AOA1 due to a homozygous mutation in the APTX gene (W279X; 606350.0006). All 3 patients responded well to CoQ10 supplementation. Thirteen additional patients with coenzyme Q deficiency did not have APTX mutations. Quinzii et al. (2005) noted that CoQ10 deficiency has been associated with 3 major clinical phenotypes and remarked that the finding of mutation in the APTX gene in these sibs supports the hypothesis that the ataxic form of CoQ10 deficiency is a genetically heterogeneous entity in which deficiency of CoQ10 can be secondary.
Le Ber et al. (2007) found decreased muscle CoQ10 in 5 of 6 patients with AOA1. Three patients who were homozygous for the W279X mutation had the lowest values. The CoQ10 deficiency did not correlate with disease duration, severity, or other blood parameters, and mitochondrial morphology and respiratory function were normal.
NomenclatureDate et al. (2001) suggested that the best name for this disorder is 'early-onset ataxia with oculomotor apraxia and hypoalbuminemia' (EAOH).
According to Dawson (2001), the syndrome of ataxia with oculomotor apraxia is sometimes referred to as Aicardi syndrome; this runs the risk of confusion with the other Aicardi syndrome, agenesis of the corpus callosum with chorioretinal abnormalities (304050).