Cerebellar Ataxia in Adults with <scp><i>SQSTM1</i></scp>‐Associated Frontotemporal <scp>Dementia–Amyotrophic</scp> Lateral Sclerosis Spectrum of Disorders

A 43-year-old Asian Indian male presented with progressive gait difficulty for 3 years. It began with a feeling of tightness in both legs and progressed to scissoring of the legs, imbalance, and veering to either side while walking. The gait difficulty did not worsen significantly in the dark or on closing the eyes. After a year, he developed bilateral proximal lower limb weakness. By the time of presentation to us, he was unable to walk unaided. He developed a slurring of speech 8 to 9 months after the onset of symptoms. During the past year, he became forgetful in conversations and during his daily activities. There was no apathy, aggression, disinhibition, visuospatial deficits, calculation deficits, delusions, or hallucinations. He did not report seizures; thinning of muscles; fasciculations; or sensory, bladder, or bowel impairment. There was no parental consanguinity. His mother had a similar illness with onset at 50 years (see Fig. 1a for details). Examination revealed an average built, right-handed person with vitiligo over both hands. Montreal Cognitive Assessment revealed a score of 24/30. On detailed higher mental function examination, he had executive dysfunction, effortful encoding, impaired retrieval of previous information, impaired semantic fluency but spared recognition, and mild depression. Cranial nerve examination revealed bilateral gaze-evoked nystagmus and spastic dysarthria. Bilateral saccades and pursuits were intact. No wasting or fasciculations were noted. There was grade 2 spasticity in all 4 limbs. Bilateral hip flexion was Medical Research Council grade 4/5, and the rest of the muscles in the upper and lower limbs were 5/5. Deep tendon reflexes were symmetrically brisk with ankle clonus bilaterally. Finger-nose-finger and heel-shin tests were impaired bilaterally, suggestive of ataxia. Sensory examination was normal. There was no tremor, rigidity, dystonia, bradykinesia, or myoclonus. He walked with a spastic gait with bilateral support, and tandem gait was impaired (Video 1). Spinocerebellar ataxias (SCAs), adult-onset leukoencephalopathies, complicated hereditary spastic paraparesis, primary progressive multiple sclerosis, and amyotrophic lateral sclerosis (ALS)–plus syndromes were considered in this patient with adult-onset cerebellar ataxia, spasticity, and cognitive impairment. Laboratory workup showed normal hemogram, liver, renal, and thyroid function tests. Vitamin B12 levels were 961 pg (normal 190–950 pg/mL). HIV 1 and 2 antibodies and a venereal disease research laboratory test were negative. Brain magnetic resonance imaging showed bilateral symmetrical, confluent posterior periventricular T2–fluid-attenuated inversion recovery (FLAIR) hyperintensities without contrast enhancement (Fig. 1c,d) and mild frontal atrophy (T1 sequence; Fig. 1e). Clinical exome sequencing revealed a heterozygous SQSTM1 splice site variant c.1166–2 A > G (NM_003900) at the junction of the intron7-exon 8 boundary (Fig. 1f). This is classified as a pathogenic variant associated with the phenotype of frontotemporal dementia (FTD)–ALS (OMIM*616437).1 This variant was also observed in his elder brother (currently asymptomatic) and younger sister (having bilateral lower limb hyperreflexia). The repeats for SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, and C9orf72-TP were screened, and no pathogenic repeats were found. No other pathogenic or likely pathogenic variants were found. FTD-ALS is an autosomal dominant neurodegenerative disorder characterized by adult-onset behavioral abnormalities, cognitive dysfunction, speech apraxia, and/or upper and lower motor neuron signs. SQSTM1 was recently designated as a candidate gene for FTD-ALS disorders.2, 3 The present case was reevaluated after the genetic report. Needle electromyogram showed normal motor unit action potentials without any spontaneous activity. Serum alkaline phosphatase and lactate dehydrogenase levels were within range, and there was no clinical evidence of bone disease. [18F]fluorodeoxyglucose–positron emission tomography images revealed hypometabolism involving both insular cortices, caudate, cerebellar hemispheres, vermis, and dentate nucleus (Fig. S1). Parental DNA was not available for segregation analysis. Mutations in sequestosome-1 (SQSTM1) were first identified in patients with Paget's disease of bone and later linked to ALS, behavioural variant Frontotemporal Dementia (bvFTD), and FTD-ALS.3 The SQSTM1 mutation is a rare cause of FTD-ALS with fewer than 50 cases described in the literature. Variability in phenotype can be noted even within the same family.3 SQSTM1 encodes p62, a multipurpose protein that participates in many cellular functions, including transcription regulation, ubiquitin-mediated autophagy, and apoptosis.4 Defective p62 aggregates and accumulates in the motor neurons, cerebral neocortex, and hippocampus as inclusions, causing neurodegeneration.5 Our report expands the known clinical spectrum of SQSTM1-associated disorders (Table S1). Our patient had no evidence of lower motor neuron disease, either clinically or electrophysiologically. Cerebellar ataxia has been reported in childhood-onset SQSTM1-associated disease,6, 7 but not in adulthood, which is a novel feature in the present case. Clinically, the upper motor neuron signs were predominant with only mild frontal and temporal lobar dysfunction. In contrast to reported patterns, imaging in our patient revealed prominent T2/FLAIR hyperintensities in the white matter. SQSTM1-associated FTD-ALS can present with clinical and imaging features suggestive of a leukoencephalopathy. Figure S2 shows a diagnostic approach algorithm for such cases. This case highlights the phenotypic heterogeneity in FTD-ALS-associated mutations, as our understanding of newly detected genes and variants evolves. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. B.M.: 1B, 2B, 2C, 3A, 3B R.R.: 1A, 1B, 2A, 2B, 3B A.G.: 1B, 1C, 2A, 3B M.F.: 1B, 2B, 3B U.S.: 1B, 2B, 3B S.P.: 1B, 2B, 3B A.G.: 1B, 2A, 2B, 3B M.T.: 1B, 2B, 3B V.Y.V.: 1B, 2B, 3B M.B.S.: 1B, 2B, 3B R.B.: 1B, 2B, 3B M.V.P.S.: 1B, 2B, 3B Written informed consent was taken from the patient's primary caregivers. The authors confirm that the approval of the institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No funding was received for this work and the authors have no conflicts to report. The authors have no disclosures to report. Figure S1 Brain [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) computed tomography (CT) images: (a) FDG PET/CT maximum intensity projection image not showing any abnormal tracer accumulation, (b–e) brain transaxial fused PET/CT images showing bilateral cerebellar hypometabolism (white arrow), mesial temporal hypometabolism (red arrow), insular hypometabolism (orange arrow), and anterior cingulate and caudate hypometabolism (green arrow). Figure S2 Diagnostic approach algorithm for patients presenting with adult onset cognitive impairment, cerebellar ataxia and other long tract signs. Table S1 Phenotypic characteristics of SQSTM1-related frontotemporal dementia–amyotrophic lateral sclerosis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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