A novel mutation in RNF216 gene in an Indian case with Gordon Holmes syndrome

Abstract

Early-onset cerebellar ataxia has a broad range of challenging differential diagnoses. Identification of hypogonadism can assist in narrowing down differential diagnosis in the presentation of progressive ataxia. Gordon Holmes syndrome as described by Sir Gordon Holmes in 1908 consists of ataxia with hypogonadism. It is due to mutation in RNF216 and OTUD4 genes which encode for enzymes in the ubiquitin-proteasome system. In this case report, we describe a 30-year-old male presenting with insidious-onset progressive ataxia with hypogonadotropic hypogonadism, cataract, pan-cerebellar atrophy with bilateral cerebral white matter hyperintensities and a positive homozygous mutation for RNF216 making the diagnosis of Gordon Holmes syndrome. The presence of hypogonadism in a patient with ataxia should alert the clinician to look for such a diagnosis.

Background

Gordon Holmes syndrome (MIM # 212840) is an autosomal recessive neurodegenerative disease of adults presenting with progressive ataxia, cognitive decline, hypogonadism and variable movement disorders.¹ Recent studies on this rare disease have identified its association with disordered protein and lipid degradation which shows the importance of further research into this disorder in identifying possible therapeutics.

Case presentation

A 30-year-old unmarried male presented with insidious-onset gradually progressive difficulty in walking, maintaining balance and change in speech for the last 5 years with frequent falls. There is no history of weakness, paresthesia, difficulty in micturition or defecation, seizure, visual symptoms or headache. He was born out of a non-consanguineous marriage with a normal perinatal and developmental history. However, there is a history of similar illness in his elder brother who had difficulty in walking and poorly developed secondary sexual characteristics.

General examination showed a pulse of 78 /min, regular, normal volume and character, blood pressure of 120/70 mm Hg and respiratory rate of 14 /min, without pallor, icterus, oedema, joint tenderness or swelling or rash. However, there was a characteristic absence of facial hairs, sparse axillary and pubic hairs with a stretch penile length of 5 cm and bilateral low testicular volume of 10 mL (figure 1A and B). Neurocutaneous markers were not seen. There was evidence of cataract in both eyes (figure 1C).

Figure 1.

Showing lack of hairs on chest (A), scanty pubic hairs with short penile length and bilateral low testicular volume (B), evidence of cataract (C), exome sequencing showing a homozygous frameshift ‘variant of uncertain significance’ variant (NM_207116.3:c.591_592insTG; p.Gln198CysfsTer43) in exon 4 of RNF216 gene in chromosome 7:5 780 885 (D).

Neurological examination showed normal higher mental functions and cranial nerves including fundus examination. Motor examination revealed normal tone, power of limbs, deep tendon reflexes and flexor plantar response. The examination of gait showed a broad-based ataxic gait, with swaying to both sides and a tendency to fall during turns. The patient also had dysmetria, dysarthria (scanning speech) and mild intention tremor in the upper limbs. Sensory examination was normal with absent Rhomberg’s sign.

Investigations

His laboratorical workup showed a normal hemogram, renal profile, liver function and electrolytes. Blood work showed hypogonadotropic hypogonadism (testosterone level of 11.39 ng/dL (normal lab range of 400–1080 ng/dL), luteinising hormone 0.11 mIU/mL (normal 1.5–9.3 mIU/mL), follicle stimulating hormone <0.3mIU/mL (normal 1.4–18.1 mIU/mL)) with normal thyroid stimulating hormone, cortisol and prolactin levels. MRI of the brain showed non-enhancing symmetric T2/FLAIR (Fluid-attenuated inversion recovery) hyperintense lesions within the subcortical white matter, thalamus and basal ganglia, with cerebellar atrophy, with no pituitary or hypothalamic lesion (figure 2). The exome sequencing showed a homozygous frameshift ‘variant of uncertain significance’ variant (NM_207116.3:c.591_592insTG; p.Gln198CysfsTer43) in exon 4 of RNF216 gene in chromosome 7:5 780 885 (figure 1D). The diagnosis of Gordon Holmes syndrome was confirmed.

Figure 2.

MRI of brain showing symmetric posterior-predominant T1 hypo-intense subcortical lesions (A), symmetric T2/FLAIR hyper-intense lesions in subcortical white matter (B,C), thalamus and basal ganglia (D), along with cerebellar atrophy (E), without any evidence of gadolinium enhancement of lesions (F).

Differential diagnosis

Among the main differentials, we kept autosomal recessive ataxia (MIM * 604490), adult-onset leucodystrophies (MIM # 300100), mitochondrial disorder (MIM # 617710) and metabolic storage disorder (MIM # 232400).

Treatment

He was treated with hormone replacement therapy (testosterone enanthate 100 mg monthly depot injection) along with gait training and speech therapy.

Outcome and follow-up

However, there was no improvement in ataxia or sexual characteristics at 6 months of follow-up.

Discussion

The clinical phenotype of ataxia with hypogonadism was first described by Sir Gordon Holmes in 1908.¹ He reported three brothers and a sister who presented with cerebellar symptoms and hypogonadism at their 30s. Their symptoms included staggering gait, incoordination of upper limbs and slurred speech. They later developed tremors and choreiform movements of the head and limbs, became bedbound and died. Autopsy results showed uniform cerebellar degeneration and considerable loss of granule cell layer among other features.

With the advent of hormonal assays, further studies have been performed into the different associated endocrine abnormalities, thereby identifying certain patterns among the patients with this phenotype, namely:

1. Hypogonadotropic hypogonadism (the most common abnormality found in Gordon Holmes syndrome).

2. Hypergonadotropic hypogonadism.

3. Isolated defects in sperm morphology without any clearly defined endocrinopathy.²

However, the genetic basis of this illness was described by the Margolin et al.³ They performed exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism and targeted sequencing of candidate genes in similarly affected patients. They identified inactivating mutations in RNF216 or the combination of mutations in RNF216 and OTUD4 as causative mutations for this phenotype. These genes encode for ubiquitin E3 ligase and a deubiquitinase, respectively, linking this disease to the ubiquitin–proteasome pathway. Recently other genes (eg, STUB1) linked to this pathway associated with a similar presentation have been identified.⁴

Gordon Holmes syndrome is also been grouped among PNPLA6 disorders (MIM * 603197) (PNPLA6 codes for neuropathy target esterase protein which is involved in the breakdown of lipids).⁵ Other members in this phenotypic continuum including Boucher–Neuhäuser syndrome (MIM # 215470) (cerebellar ataxia, chorioretinal dystrophy and hypogonadotropic hypogonadism); Oliver–McFarlane syndrome (MIM # 275400) (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability and hypopituitarism); Laurence–Moon syndrome (MIM # 245800); and spastic paraplegia type 39 (MIM # 612020) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia).⁶ Adult-onset leucodystrophies are close genetic mimics with predominant central white matter involvement presenting with ataxia, cognitive impairment, movement disorders, encephalopathy, stroke, parkinsonism, brainstem affection, visual abnormality, etc.⁷

In a previous case report by Verma et al⁸, Gordon Holmes syndrome was diagnosed in a 26-year-old male with pure pan-cerebellar syndrome and hypogonadism; however, cataract and white matter involvement of the cerebral cortex was not described in it. This observation requires further research to identify pathogenic pathways, which can lead to developing effective therapeutics, as current management for the patient population is limited to supportive care (including physiotherapy and hormone replacement therapy). Durmaz Celik et al⁹ recently identified a novel homozygous frameshift mutation (ENST00000389902.3):c.1860_1861dupCT (p.Cys621SerfsTer56) in exon 12 of the RNF216 gene in their case presenting with hypogonadotropic hypogonadism, ataxia, cognitive decline, parkinsonism and dystonia. He further reviewed the genetic basis of GHS and emphasised the pathophysiology of genotype–phenotype correlations with respect to different variants in GHS.

Learning points.

• Gordon Holmes syndrome should be considered in the differential diagnosis of rapidly progressive ataxia, hypogonadotropic hypogonadism, cataract and subcortical white matter lesions in neuroimaging.

• Early recognition and work-up can prevent such florid presentation and reduce disease morbidity.

• Genetic sequencing can benefit in the exploration of chronic ataxias.

• Future research can help in the possible illustrations regarding the different axis of involvement in Gordon Holmes syndrome.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).