Spinocerebellar Ataxia 2 and 12 Mutations in an Indian Family with Cerebellar Ataxia and Slow Saccades

SCAs are a class of tandem nucleotide repeat expansion (TNRe) disorder, with certain forms more prevalent in certain ethnic populations (SCA10 and 12) and others showing a more cosmopolitan prevalence (SCA1–3, 6–8, and 17).1 More than one type of SCA mutation in single patient/kindred has rarely been reported, although there is some literature evidence showing the coexistence of SCA mutations where one coding TNRe is associated with another noncoding TNRe, for example, SCA8 (CTGe in 3′ untranslated region [UTR]) with SCA6, 1, or 3 (CAGe‐coding region)2, 3, 4 and SCA2 (CAGe‐coding region) with SCA10 (ATTCTe‐intronic region).5 The only known exception to this is the coexistence of SCA3 and 17 TNRe, both in the coding region.6

Here, we report, for the first time, the co‐occurrence of SCA2 and 12 mutations (two most common forms of SCAs in the Indian population)7 in 2 patients of an Indian family manifesting cerebellar ataxia (CA), slowing of saccades, and other neurological deficits.

Case Report

The proband of the family, a 47‐year‐old female (case‐II:2; Fig. 1) with maternal ancestral origin in Haryana (state of northern India) was registered in our clinic with a 7‐year history of progressive development of gait ataxia and complaints of speech slurring, upper‐limb incoordination for the last 5.5 years, and head tremor for the last 2 years. Neurological examination revealed severe slowing of saccades, mild hypotonia, upper‐limb areflexia, and Babinski's sign. Strength was normal in all limbs, but proprioceptive and vibration senses were impaired. Moderately severe gait ataxia, moderate degree of intention tremor in upper‐limbs, head tremor, dysarthria, and facial myokymia were also noted. Brain MRI revealed bilateral cerebellar and brain stem atrophy (Fig. 1). Regular follow‐up (2009–2012) showed progressively increasing ataxia with severity scores (international cooperative ataxia rating scale; ICARS) of 49 (2009), 50 (2010), 52 (2011), and 55 (2012) of 100 (Table 1).

Figure 1.

Pedigree chart of the family and radiological findings among the affected. (A) Describing disease affected status and below the symbols are CAG length changes in SCA2 and 12 mutation, age of the individual, and age at onset. Dark symbols indicate affected individuals; blank symbols represent unaffected; and diamond symbols have been used to anonymize the identity of the individuals. (B) (a–c): case‐II:2 axial T1 image (a), T2 (b) at the level of middle cerebellar peduncle show atrophy of pons and prominent cerebellar follia, and sagittal T1W (c) shows flattening of pons and small medulla. A–C: case‐II:1 Cerebellum and brain stem atrophy, especially in pons and medulla (B); (d): case‐II:7 NCCT at the level of brain showing diffuse brainstem and cerebellar atrophy (B); (e and f): T2W axial and sagittal view (Case‐III:2) showing cerebellum and brainstem atrophy (particularly of pons and medulla; flattening of pontine bell is noticed). This patient is younger; however, extent of atrophy is more severe.

Table 1.

Details of various neurological impairments in the affected individuals of the family

Parameter	Case‐II:2 (2009)	Case‐II:5 (2013)	Case‐II:7 (2013)	Case‐III:2 (2013)
Age at examination	47	45	42	29
Age at onset	40	32	30	23
Disease duration	7	13	12	6
Gender	F	M	M	F
Genetic impairment	SCA2‐(CAG)41 and SCA12‐(CAG)48	SCA2‐(CAG)41 and SCA12‐(CAG)48	SCA2‐(CAG)41	SCA2‐(CAG)44
Cerebellar findings
Gait ataxia (onset)	40	32	30	23
Intention tremor (onset)	42.4	39	36	25
Dysarthria (onset)	42.5	39	37	25
Head tremor (onset)	45	−	−	−
Nystagmus	Absent	Absent	Absent	Absent
Walking aid (onset)	−	41	−	−
Dysdiadokokinesia	+	+	+	+
Motor system
Wasting	Absent	Absent	Absent	Absent
Power	5/5 all limbs	4/5 knee flexors, rest 5/5	5/5 all limbs	5/5 all limbs
Tone	Normal to hypotonic	Normal	Normal	Normal
Reflexes	+ (UL)/++(LL)	++(UL)/+++(LL)	+(Rt) to ++ (Lt)	+ +(UL)/+++(LL)
Plantar	↑↑	↓↓	↓↓	↓↓
Extrapyramidal findings
Rigidity	Absent	Absent	Absent	Absent
Dystonia	Absent	Absent	Absent	Absent
Rest tremor	Absent	Absent	Absent	Absent
Bradykinesia	+ (Mild)	+ (Mild)	+ (Mild)	+ (Mild)
Slow muscular twitching movements in the infraorbital region (likely facial myokimia)	+	Absent	Absent	Absent
Oculomotor abnormalities
Slow saccades	+++	++	++	++
Broken pursuit	−	−	−	−
Ophthamoplegia	−	−	−	−
Other relevant observations
Dysphagia	−	+	−	−
Autonomic dysfunction	++	−	+	−
Psychiatric symptoms	−	Suicidal tendency	−	−
Hearing impairment	−	−	+	−
Peripheral nervous system
Proprioception	Impaired	Normal	Normal	Normal
Vibration senses	Impaired	Normal	Normal	Impaired
Nerve conduction studies	Normal	ND	Normal	ND
MMSE scores	26/30	ND	ND	ND
ICARS scores
Posture and gait disturbances (total score: 34)	17, 18, 21, 23a	15	14	18
Kinetic function (total score: 52)	28, 28, 26, 27a	15	13	22
Speech disorder (total score: 8)	3, 3, 4, 4a	3	3	4
Oculomotor (total score: 6)	1, 1, 1, 1a	0	0	0
Total score: 100	49, 50, 52, 55a	33	30	44
MRI	Cerebellar and brain stem atrophy	NA	Cerebellar and brain stem atrophy	Cerebellar and brain stem atrophy
Cardiac autonomic function tests	Severe loss of autonomic tone and mild loss of parasympathetic reactivity	ND	Severe loss of autonomic tone	ND

^aRepresents ICARS scores on follow‐up evaluations during 2009–2012.

MMSE,Mini–Mental State Examination; ND, not done; NA, not available.

Her family history was positive for ataxia—her 2 siblings (case‐II:5 and case‐II:7) and a daughter (case‐III:2; Fig. 1, pedigree chart) were also affected. The proband's mother (Case‐I:2) died at 63 years of age with a history of ataxia (onset age: 45 years), aggressive temperament, and suicidal tendency, and the proband's father (case‐I:1), 78 years of age, gave no history of neurological illness. The evaluation of other affecteds revealed variability in age of onset (case‐II:5: 32 years; case‐II:7: 30 years; case‐III:2: 23 years) and other neurological features (Table 1).

Genetic analysis of the available subjects (Fig. 1) showed mutation in both ATXN2‐41CAG (SCA2) and PPP2R2B‐48CAG (SCA12) repeats in the proband and case‐II:5. Case‐II:7 had ATXN2‐41CAG, and case‐III:2 had ATXN2‐44CAG repeats (positive only for SCA2). None of the unaffected family members carried the CAG mutation in either of the genes. SCA1, 3, 6, 7, 8, and 17 mutations were screened negative in the family.

SCA2 and 12 mutations are located on two separate chromosomes (12p13.1 and 5q31.1, respectively). SCA2 is caused by CAG repeat expansion (>32) in the coding region of ATXN2 (12q24.1), and its typical clinical features include CA, severe slowing of saccades, postural tremors, upper‐limb arreflexia, and myoclonus. Brain MRI of SCA2 patients shows hemispheric cerebellar atrophy and brain stem atrophy.8 SCA12, a rare subtype of SCAs, shows autosomal dominant inheritance pattern. Caused by CAG repeat expansion (>51) in the 5′ UTR of PPP2R2B gene (5q31‐5q32),9 SCA12 is uniquely prevalent among patients having an ancestral origin in the Haryana state of northern India.10 In general, disease starts in the fourth to fifth decade and progresses slowly with prominent action tremor of hands (symmetric or asymmetric) as a symptom at onset and late development of gait ataxia, speech impairment, and head tremor, which may also be dystonic and precede hand tremor.11 Other neurological findings observed are hyper‐reflexia, parkinsonism, dystonia of head, myokimia, and dementia. Brain MRI shows cerebrocerebellar atrophy.9, 10, 11

To the best of our knowledge, the coexistence of SCA2 and 12 in this family is the first report describing this particular combination of mutations. The common phenotype of individuals (proband and case‐II:5) with both SCA2 and 12 mutations in this family was CA and slowing of saccades (typical SCA2 features). Interestingly, both patients did not manifest action tremor of the hands, a characteristic feature of SCA12; however, the proband had head tremor and facial myokymia. The latter two findings, along with gait ataxia, are shared features for both SCA2 and 12. The other 2 affecteds of the family who carried only SCA2 mutation had CA, slow saccades, and upper‐limb hyporeflexia. Therefore it is difficult to ascertain whether the phenotype of the individuals with a coexisting mutation would have a combined effect of SCA2 and 12 or manifest only SCA2‐like features. However, the latter condition seems more likely, because SCA12 is generally a late‐onset (fourth to fifth decade) disorder, and the clinical phenotype is also more suggestive of SCA2.

This report suggests that the possibility of coexisting SCA mutations should be considered for patients with atypical manifestations and/or for patients who are at risk for ethnicity‐specific SCA subtype (SCA12 in this family). Finding SCA2 and 12 in this family would have implications for establishing the prognosis, genetic testing strategy, genetic screening, and genetic counselling.

Further follow‐up of the family would be necessary to understand the disease course, management of neurological complications, and the interacting network of pathology in these SCAs.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

M.F.: 1A, 1B, 1C, 2B, 3A

S.S.: 2B

A.G.: 1C

A.K.S.: 1A, 1B, 1C, 3A

Disclosures

Funding Sources and Conflicts of Interest: This study was conducted under resources from the Council of Scientific and Industrial Research (research grant SIP0006). A senior research fellowship (for S.S.) from an Indian Council of Medical Research project grant (5/4‐5/75/neuro/2012‐ncd‐I) is duly acknowledged. The authors report no conflicts of interest.

Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.