Late‐Onset Tay‐Sachs Disease in an Irish Family

ABSTRACT

Background

Late‐onset Tay‐Sachs disease (LOTS) is an autosomal‐recessive lysosomal storage disease caused by deficient β‐hexosaminidase A activity. LOTS is rare in the Ashkenazi Jews, but even rarer in the non‐Jewish population.

Cases

We report an Irish family expanding the LOTS phenotype (ataxia, diffuse muscle wasting, dystonia, chorea, belly dancer's dyskinesia, and neuropsychiatric features) associated with the known HEXA variant 1073 + 1G > A and a novel variant c.459 + 24G > C.

Conclusions

LOTS should be considered in patients with similar symptoms and cerebellar atrophy on brain imaging.

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Late‐onset Tay‐Sachs disease (LOTS) is an autosomal‐recessive disorder attributed to HEXA mutations causing reduced β‐hexosaminidase A activity and subsequent CNS ganglioside accumulation. Affected individuals can present from late childhood with slowly progressive and heterogenous clinical manifestations such as cerebellar dysfunction, anterior horn cell pathology mimicking spinal muscular atrophy, and extrapyramidal and psychiatric features. ¹ LOTS is rare in the Ashkenazi Jewish (1:135,000). ¹ In the non‐Jewish, LOTS is much scarcer and associated with extreme mutation heterogeneity, often with private or unique alleles. ² We report an Irish family with LOTS, harboring a novel HEXA variant, and present videos of 3 siblings demonstrating heterogenous clinical manifestations including extrapyramidal, spinocerebellar, and neuropsychiatric involvement.

Case Series

A family pedigree showing genotypes are illustrated in Figure 1. Clinical, biochemical, and MRIbrain characteristics for patients II.4, II.5, II.6, and II.9 are illustrated in Table 1.

FIG. 1.

Family pedigree (A). Brain magnetic resonance imaging (sagittal T2) shows marked cerebellar atrophy in case 1 (II.4, proband) (B) and marked cerebellar and frontal lobe atrophy in case 2 (II.5) (C).

TABLE 1.

Clinical, biochemical, and brain imaging characteristics of 4 Irish siblings with LOTS

Phenotypic characteristics	Case 1 (II.4)	Case 2 (II.5)	Case 3 (II.6)	Case 4 (II.9)
Sex/age at last exam	M/52	F/54	F/44	F/30s
Age at symptom onset	Late 30s	Early 20s	Late teens	Mid‐teens
Clinical symptoms and signs
Dysarthria	Moderate	Severe	Moderate	Severe
Appendicular ataxia	Moderate	Moderate	Mild	NK
Gait ataxia	Independent‐impaired gait	Device‐dependent gait	Independent‐impaired gait	WCB × 6 years predeath
Muscle wasting	+	−	−	NK
Spasticity	−	−	−	NK
Tendon reflexes	Increased	Increased	Normal	NK
Plantar responses	Extensor	Flexor	Flexor	NK
Frontal release signs	−	Grasp reflex	−	NK
Movement disorder	Axial and distal limbs dystonia, right hand chorea, “belly dancer's dyskinesia”	Axial dystonia	Mild postural hand tremor	NK
Ocular movements	Normal	Impaired smooth pursuit/jerky pursuits	Impaired smooth pursuit and fixation, hypermetric saccades	NK
Fundoscopy	Optic pallor	Optic pallor	Normal	NK
Urinary incontinence	+	+	−	+
Epilepsy	−	+	+	+
Mental retardation	Mild	Moderate	Mild	Moderate
Neuropsychiatric	Mild behavioral changes in adulthood	Bipolar disorder, moderate behavioral changes in adulthood	Schizophrenia, depression	Psychotic episodes, severe behavioral changes since mid‐teens
MMSE	23/30	17/30; FAB 2/18	23/30	Severe cognitive impairment
Initial diagnosis	Mild mental retardation Spinocerebellar ataxia	Moderate mental retardation Mood disorder	Mild mental retardation Schizophrenia Mood disorder	Severe mental retardation Cerebellar ataxia
β‐hexosaminidase activity
Leucocytes (NR 134–700 nmol/hr/mg)	NK	29	15	28
Plasma (NR 76–269 nmol/hr/ml)	4.6	11	4	7
Brain MRI	Marked cerebellar atrophy	Marked cerebellar and frontal atrophy	ND	Marked cerebellar atrophy

M, male; F, female; NK, not known; WCB, wheelchair bound; MMSE, Mini‐Mental State Exam; FAB, Frontal Assessment Battery; NR, normal range; MRI, magnetic resonance imaging; ND, not done.

Genetic Analysis

Molecular analysis of the HEXA gene was performed at the Department of Clinical Genetics Amsterdam, the Netherlands. All coding sequences of the HEXA gene, including the flanking intron sequences, were analyzed by direct sequencing. Large deletions or insertions were excluded using Multiplex Ligation Dependent Probe Amplification analysis P199 from MRC Holland (www.mrc-holland.com).

HEXA gene DNA analysis detected a previously reported heterozygous mutation c. 1073 + 1G > A and a previously unpublished c.459 + 24G > C variant in all 4 affected siblings (II.4. II.5, II.6, and II.9). The mother (I.2) was heterozygous for c. 1073 + 1G > A. An unaffected sister (II.10) tested negative for both variants. The rest of the family members were not available for testing (Fig. 1A). The variant c.459 + 24G > C has not been described before, and as splicing prediction modules (Alamut Visual 2.7.1) did not predict splicing defects, it is classified as class 3 (pathogenicity unclear).

Case 1 (II.4 Proband)

This 56‐year‐old man, born to nonconsanguineous parents of non‐Jewish European ancestry, presented with a 10‐year history of progressive dysarthria, gait ataxia, and diffuse muscle wasting. He had mild learning disability in childhood and then developed aggressive behavior with alcohol excess and urinary urge incontinence in adulthood. Birth history and early development were normal. He was initially diagnosed with spinocerebellar ataxia and mild mental retardation. Genetic tests for spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6), Freidreich's ataxia, and dentatorubral‐pallidoluysian atrophy were negative. At age 52, examination findings included generalized muscle wasting, hyperkinetic movement disorder including “belly‐dancer's dyskinesia,” pyramidal and cerebellar signs (Video S1), and mild cognitive impairment. A brain MRI showed marked cerebellar atrophy (Fig. 1B).

Case 2 (II.5)

This 54‐year‐old sister developed progressive dysarthria and ataxia in her early 20s. She has a history of mild learning disability, bipolar disorder, epilepsy, frequent lower respiratory tract infections, and urinary urge incontinence. Her mobility has gradually declined over the years with increasing ataxia and frequent falls requiring a walking aid. Her cognition and behavior have also declined, and she has lived in a nursing home since her late 40s. Examination findings included frontal lobe signs, axial dystonia, cerebellar signs, and device‐dependent ataxic gait (Video S2). Mini‐Mental State Exam score was 17/30 (moderate cognitive impairment) featuring a frontal predominant pattern (orientation, 5/10; registration, 3/3; attention/concentration, 0/5; recall, 3/3; language, 6/8; and copying, 0/1). The Frontal Assessment Battery score was very low at 2/18 (similarities, 0/3; lexical fluency, 0/3; motor series, 2/3; conflicting instructions, 0/3; go–no go, 0/3; and prehension behavior, 0/3). Brain MRI showed marked cerebellar and frontal lobe atrophy (Fig. 1C).

Case 3 (II.6)

This younger sister had mild learning disability. She left secondary school at age 16 and worked in a restaurant for a few years until she developed severe depression. At age 19, she was diagnosed with schizophrenia and was an inpatient in a psychiatric hospital for 8 years. She has lived in a residential home since her early 30s. She has a longstanding speech impediment. In the past 5 years, she developed subtle hand clumsiness, incoordination, and hand tremor. Examination findings included a flattened affect, cerebellar signs (Video S3), and mild cognitive impairment.

Case 4 (II.9 Deceased)

This youngest sister was the most severely affected. She was the first in the family to be diagnosed with LOTS at age 36. She was full‐term normal delivery and had motor and speech delays as a child (walked at 2 years and started speaking at 3 years). She attended mainstream school from age 5 but required remedial teaching. At age 15, she had a severe psychotic episode characterized by marked agitation, paranoia, delusions, and morbid thoughts. In the following 3 years, she had several admissions to psychiatric hospitals with deteriorating behavior (running away from home, temper tantrums, shouting, and crying). Over the years, she progressed to develop speech impairment, gait ataxia, seizures, and cognitive and increasing psychiatric difficulties. Brain MRI revealed cerebellar atrophy. At age 36, she was reevaluated by a pediatric and an adult neurologist. In view of the history of motor and speech delays as a child followed by progressive ataxia, cognitive and increasing psychiatric difficulties, seizures, cerebellar atrophy on MRI, family history of learning disability, and later on behavioral/psychiatric problems, an inherited metabolic condition was suspected. Lysosomal enzymes revealed very low β‐hexosaminidase A level measured in both leucocytes and plasma (case 4; Table 1), confirming the diagnosis of Tay‐Sachs disease (late‐onset form). She died at age 41 and was wheelchair‐bound for 6 years prior to her death.

Case 5 (II.1 Deceased)

This eldest brother had moderate mental handicap. He developed behavioral problems in his teens followed by progressive gait ataxia and seizures. He required full‐time care from age 18 and died at age 51 from lung cancer.

Discussion

We describe an Irish family with LOTS exhibiting marked intrafamilial variation in terms of disease onset, severity, and clinical phenotype. Similar to previous reports, no correlation was found between time of disease onset and disease severity in this family. All affected siblings progressed to develop cerebellar gait ataxia of varying severity, with 1 sibling who lost ambulation in her early 30s at the extreme of the spectrum. One sibling had a hyperkinetic movement disorder featuring dystonia, chorea, and belly dancer's dyskinesia; the latter previously unreported in LOTS. The same patient was the only patient in this family to have diffuse muscle wasting.

Psychiatric manifestations occur in 30% to 50% of LOTS, and in some patients can dominate the clinical presentation and disease course. All affected siblings in this family had neuropsychiatric problems of various degrees, with this being the presenting feature in 2 cases (II.6, II.9). Cognitive impairment ranging from mild to severe global cognitive decline and dementia was previously reported in LOTS. ³ One study found cognitive impairment limited to memory and executive functioning. ⁴ In our family, there was a wide range of cognitive impairment (mild to severe); 1 patient had frontal predominant features coupled with marked frontal atrophy on MRI (case 2, II.5). Severe global cognitive impairment including frontal lobe dysfunction was previously reported in a 17‐year‐old with LOTS. ⁵ However, frontal lobe predominance, similar to our case, is previously unreported. Although eye movement abnormalities are not a classic feature of LOTS, they have been described ⁶ as was evident in 2 of our siblings. Similar to previously reported MRI findings, severe cerebellar atrophy was found in 3 of our imaged patients. ⁷

A common allele (c.1073 + 1G > A) was found in non‐Jewish Whites originating from the United Kingdom, Ireland, and Western Europe. ⁸ Patients with LOTS are usually heterozygous for 1 severe and 1 mild HEXA mutation. ⁹ All 4 affected siblings from our family harbored the common deleterious Irish mutation (c.1073 + 1G > A) as well as an unknown previously unpublished variant (c.459 + 24G > C). The mother was a heterozygous carrier for the common mutation (c.1073 + 1G > A) and an unaffected sister (II.10) tested negative for both mutations, arguing for a potential pathogenic role of the new variant (c.459 + 24G > C). The mother (I.2), deceased at age 79, had multiple comorbidities, including chronic pulmonary obstructive disease, bowel cancer with hemicolectomy, atrial fibrillation, recurrent strokes, and dementia.

LOTS is more frequent in Ashkenazi Jewish but can very rarely occur in non‐Jewish populations. The diagnosis of LOTS ought to be considered among patients presenting with cerebellar signs, cerebellar atrophy on brain imaging (Fig. 1B), dystonia, chorea, motor neuron signs, and dementia and in those with psychiatric disorders (psychosis, depression, bipolar disorders) even when focal neurologic deficits are absent. Clinical manifestations can emerge in various combinations over the years, and a positive family history is a valuable clue. The diagnosis is confirmed on the demonstration of β‐hexosaminidase deficiency (<15%) in the plasma or blood leukocytes. Molecular genetic testing of the HEXA gene can be used to identify the specific mutations present. ¹⁰

We describe LOTS in an Irish family, contributing new knowledge regarding the natural evolution, genotype, and clinical heterogeneity (illustrated with videos) of this rare condition.

Author Roles

(1) Clinical Examination: A. Conception, B. Organization, C. Execution; (2) Videotaping and Editing: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

S.L.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

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

B.S.: 1C, 2C, 3A, 3B

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

Disclosures

Ethical Compliance Statement

All investigations performed in this family were done in the course of clinical practice and care of the patients; therefore, ethics committee approval was not sought. Authors confirm that a written informed consent was obtained from all patients who had video recording. Written consent is with the authors. 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.

Funding Sources and Conflict of Interest

No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months

The authors declare that there are no additional disclosures to report.

Supporting information

Video S1 (II.4, proband). The video demonstrates ataxic dysarthria, generalized muscle wasting without fasciculations, axial and distal extremities dystonia, right hand chorea, abdominal wall dyskinesia “belly‐dancer's dyskinesia,” upper limb appendicular ataxia without dysmetria, dysdiadochokinesis, and a broad‐based ataxic gait.

Video S2 (II.5). The video demonstrates frontal lobe signs (staring appearance, speech perseveration and impulsivity, palilalia, grasp reflex), severe dysarthria, horizontal jerky pursuit eye movements without nystagmus, axial dystonia, upper limbs appendicular ataxia with dysmetria, dysdiadochokinesis, and device‐dependent ataxic gait.

Video S3 (II.6). The video demonstrates a flattened affect, ataxic dysarthria, impaired smooth pursuit and fixation, hypermetric saccades, upper limb appendicular ataxia without dysmetria, dysdiadochokinesis, and mild truncal ataxia.