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J Neurol Neurosurg Psychiatry. 2007 September; 78(9): 1009–1011.
PMCID: PMC2117868

Peripheral neuropathy in chromosome16q22.1 linked autosomal dominant cerebellar ataxia

Autosomal dominant cerebellar ataxia (ADCA) includes heterogeneous neurodegenerative diseases with or without various neurological signs and symptoms. Ishikawa et al reported a new type of ADCA, named chromosome16q22.1 linked ADCA (16q‐ADCA), attributed to a heterozygous C→T substitution in the 5′ non‐coding region of puratrophin‐1 gene.1 We searched for this mutation in168 patients from 129 families with ADCA and found it in six patients. The patients generally showed late onset pure cerebellar ataxia similar to previous reports1,2 but two had mild axonal neuropathy and orthostatic hypotension (OH). Our results suggest that 16q‐ADCA shows a broader clinical presentation than previously thought.

Case report

Patient No 1

An 81‐year‐old Japanese woman had dysarthria at 52 years of age, unsteady gait at 56 years, limb ataxia at 76 years and severe truncal ataxia, requiring a wheelchair. Her family history included progressive ataxia in her older sister, younger brother and son. She had cervical spondylosis at the C3–C7 level. Ocular movement was almost normal. The score on the International Cooperating Ataxia Rating Scale3 (ICARS) was 66/100. Deep tendon reflexes (DTRs) were increased, with extensor plantar reflexes. Sensation of pain was almost normal, while vibratory sensation was moderately disturbed in the lower limbs. Passive head up tilt testing (HUT) performed at 60° for 30 min revealed OH, with a slightly increased pulse rate (table 11).

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Table 1 Data from nerve conduction study and test of autonomic nervous system in the two patients

Patient No 2

A 58‐year‐old man, the son of patient No 1, had dysarthria and imbalance at 52 years of age. He had no cervical spondylosis. At 58 years he had scanning speech, normal ranges of ocular movement with gaze evoked nystagmus, and mild limb and truncal ataxia. The ICARS score was 25/100. DTRs were normal, without abnormal plantar reflexes. Pain sensation was almost normal, while vibratory sensation was mildly disturbed in the lower limbs. The autonomic system was nearly normal, except for OH (table 11).

Genetic analysis was performed after obtaining patient informed consent. The results ruled out spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, 8, 12 and 17, as well as dentatorubral pallidoluysian atrophy. PCR amplification and EcoNI restriction fragment length polymorphism or sequence analyses of the puratrophin‐1 gene revealed a heterozygous C→T substitution at 16 nt upstream of the putative translational initiation site,1 as found in four of the 168 patients from the 129 families with ADCA. We analysed 10 microsatellite markers around the puratrophin‐1 gene (GGAA05, GGAA10, GATA01, D16S421, TA001, CATG003, 17msm, CTTT01 and D16S3095) using an ABI 3100‐Avant genetic analyser (Applied Biosystems, Foster City, California, USA).1 All patients shared a haplotype “1‐3‐2‐3‐1‐4‐2” for markers16cen‐GGAA05‐GGAA10‐GATA01‐D16S421‐TA001‐CATG00317msm‐16qter, which matched a reported founder haplotype between GATA01 and 17msm.1 This finding suggested that 16q‐ADCA shows a strong founder effect and that our atypical cases have similar genetic backgrounds. Brain MRI showed atrophy of the cerebellum, but not of the brainstem, in patient Nos 1 and 2. The results of electrophysiological tests, tilt tests and 123I‐meta‐iodobenzylguanidine myocardial scintigraphy (123I‐MIBG‐scintigraphy) are summarised in table 11.. Audiograms were almost normal. Needle EMG revealed increased amplitude and prolonged duration of motor units without increased spontaneous activities in the tibialis anterior or extensor hallucis longus muscles. Neither patient had systemic diseases or conditions, including diabetes mellitus, malnutrition, ischaemic heart disease or collagen disease. They were receiving no medications with potential effects on the autonomic nervous system.


The results of nerve conduction studies (NCS) in patient Nos 1 and 2 revealed reduced compound muscle action potentials (CMAPs) with slightly or mildly decreased nerve conduction velocities, indicating axonal sensorimotor neuropathy.4 Because aging can affect the outcome of NCS, the results for patient No 1 (81 years) were compared with those for 107 elderly controls (table 11).). Needle EMG findings were consistent with involvement of peripheral motor nerves. Clinically, our patients had normal pain sensation but disturbed vibratory sensation, suggesting large fibre dominant axonal neuropathy. Delayed cortical potential with unevoked potential in the lumbar region on short sensory evoked potentials (SSEP) together with normal distal sensory nerve velocities in patient No 1 suggested involvement of proximal peripheral nerves. Alternatively, sensory systems might have been centrally affected. Three of the other four patients with 16q‐ADCA showed decreased DTRs in four limbs, which may reflect peripheral neuropathy, while patient No 1 had increased DTRs with extensor plantar reflexes. These pyramidal signs as well as abnormal SSEP may be ascribed to her severe cervical spondylotic myelopathy rather than 16q‐ADCA, as they were absent in patient No 2, the son of patient No 1. However, we cannot rule out that such central sensorimotor involvement might have developed over a longer duration of 16q‐ADCA in patient No 1. In addition to polyneuropathy, patient Nos 1 and 2 had OH. On HUT, increased plasma arginine–vasopressin concentrations and renin activity suggested that their OH was not due to involvement of the central autonomic nervous system. In patient No 1, abnormal QTc intervals and dispersion suggested involvement of the cardiac post‐ganglionic sympathetic nervous system, which was supported by the abnormal findings of 123I‐MIBG‐scintigraphy. Unfortunately, the other four patients with 16q‐ADCA did not return to our hospital to undergo NCS or tests for OH because of severe disability. Our findings are inconsistent with those reported for 16q‐ADCA, but agree with those found in many other types of ADCA. Van de Warrenburg et al reported a high prevalence (70.4%) of peripheral nerve involvement in patients with SCA1, 2, 3, 6 and 7.4 Sensory or sensorimotor axonal neuropathy is also associated with other types of ADCA, including SCA14.5 OH is found in SCA1 and SCA3.5 Collectively, available evidence suggests that 16q‐ADCA may also involve nervous systems unrelated to the cerebellum, although only small numbers of patients have been studied.

In summary, we demonstrated that 16q‐ADCA can be associated with peripheral neuropathy and OH, extending the clinical presentation of this disease. A previous study reported that SCA4, an ataxia closely linked to a nearby locus to the one affected in 16q‐ADCA, is clinically distinct from the latter disease because of the presence of sensory axonal neuropathy and pyramidal signs.1 However, our findings may suggest that SCA4 and 16q‐ADCA are allelic. Further clinical studies and genetic analyses may help to establish these diseases as new clinical entities.


Competing interests: None.


1. Ishikawa K, Toru S, Tsunemi T. et al An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single‐nucleotide substitution in the 5′ untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine‐nucleotide exchange‐factor domains. Am J Hum Genet 2005. 77280–296.296 [PubMed]
2. Owada K, Ishikawa K, Toru S. et al A clinical, genetic, and neuropathologic study in a family with 16q‐linked ADCA type III. Neurology 2005. 65629–632.632 [PubMed]
3. Trouillas P, Takayanagi T, Hallett M. et al International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 1997. 145205–211.211 [PubMed]
4. van de Warrenburg B P, Notermans N C, Schelhaas H J. et al Peripheral nerve involvement in spinocerebellar ataxias. Arch Neurol 2004. 61257–261.261 [PubMed]
5. Manto M U. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 2005. 42–6.6 [PubMed]

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