Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

Hereditary spastic paraplegias (HSP) are a clinically and genetically diverse group of disorders characterized by progressive lower limb spasticity. Inheritance can be dominant, recessive or X-linked, or rarely mitochondrial [1]. Additional neurological manifestations include optic atrophy, cerebellar ataxia, and peripheral neuropathy [2]. SPG79 is caused by homozygous or compound heterozygous mutations in UCHL1, which encodes Ubiquitin C‐terminal hydrolase‐L1. In addition to spasticity, ataxia, and peripheral neuropathy, SPG79 is characterized by severe optic atrophy in the first decade of life. To date, mutations in UCHL1 have been described in only three families [3‐5].

Patient 1 (P1) and Patient 2 (P2) were born to British parents from the North of England. There is no information on consanguinity. P1 was the product of a normal pregnancy and was born at full-term, and had normal early development. She first presented aged 8 years with visual problems and optic atrophy was detected. Her motor function gradually deteriorated over the next years and she developed progressive lower limb spasticity, foot deformities, and severe scoliosis requiring spinal surgery aged 16 years. Cognitive function was normal. She became non-ambulant following a femoral fracture aged 38 years. From the age of 39, she developed nocturnal hypoventilation and was commenced on overnight non-invasive ventilation.

On examination aged 41 years (Fig. 1a), she had facial dysmorphism including low nasal bridge, micrognathia, and large, low-set ears, bilateral optic atrophy and severely reduced visual acuity, but no ophthalmoparesis or nystagmus. Deep tendon reflexes were absent in the upper and lower limbs, and there was length-dependent atrophy and sensory loss in-keeping with a peripheral neuropathy. She had marked lower limb spasticity, extensor plantar responses and ankle clonus, and a severe scoliosis.

P2, her younger brother, also presented in early childhood with reduced visual acuity. He developed lower limb spasticity, contractures, and foot deformity. He became non-ambulant aged 8 years following surgical correction of his foot deformity. His visual acuity continued to deteriorate due to optic atrophy, so that he was functionally blind. Cognitive function was also unaffected in P2.

Examination of P2 aged 33 (Fig. 1a) revealed bilateral optic atrophy, both pendular and gaze induced nystagmus, ophthalmoparesis, facial dysmorphism including low nasal bridge, micrognathia and large, low-set ears, and facial hypotonia. Deep tendon reflexes were pathologically reduced in upper and lower limbs, and plantar responses were extensor. Sensation was intact. He had severe finger–nose ataxia, dysdiadochokinesia, and truncal ataxia.

Detailed laboratory work-up (including acylcarnitines, urinary organic acids, very long chain fatty acids, pristanic and phytanic acids, lysosomal enzymes, copper, caeruloplasmin, and acanthocytes) was normal. CSF constituents were normal in both cases. MRI brain in P1 aged 41 years showed mild global atrophy and a small focus of non-specific periventricular T2 signal change at the right frontal horn (Fig. 1b). MRI brain in P2 aged 34 (Fig. 1b) demonstrated no significant abnormality apart from mild increased T2 signal in the peritrigonal white matter bilaterally. Unfortunately, neurophysiological testing was not technically possible due to the degree of foot deformity and swelling. Direct sequencing of FXN revealed no candidate pathogenic variants. Fifty-six gene inherited peripheral neuropathy panel (Bristol genetics laboratory) which also failed to identify any pathogenic variants and a comparative genomic hybridization (CGH) array was normal.

Given the symptomatic features of a possible mitochondrial disorder, in particular optic atrophy, a cardiac evaluation was carried out in both patients. Echocardiogram in P2 aged 33 years revealed a small, globally hypertrophied left-ventricular cavity, left-ventricular systolic ejection gradient (36 mmHg), and impaired diastolic left-ventricular function. Echocardiogram in P1 aged 41 years was technically difficult due to severe scoliosis, but also demonstrated cardiomyopathy, with moderately impaired left-ventricular function. The left-ventricular posterior wall was hypokinetic and the interventricular septum was dyskinetic. There was no significant family history of sudden cardiac death, arrhythmias, heart failure, or young stroke.

Both siblings were commenced on ACE inhibitors and beta-blockers and their cardiac function stabilized. Despite this, both siblings developed progressive shortness of breath and apnoeic episodes. P1 died aged 43 years, P2 aged 40 years, both due to sudden cardiac death.

WES analysis revealed the presence of a homozygous c.627_629del; p.(Gly210del) UCHL1 variant (NM_004181.5) in P1 and P2 (Fig. 2a). This variant is reported only once in heterozygous form in gnomAD (allele frequency 0.000004), but never in homozygous form. Their unaffected mother was heterozygous for the variant. This variant could disrupt substrate binding at the distal UCHL1 site [9]. Additionally, we assessed IBD regions by the detection of > 1 Mbp runs of homozygosity (ROH). Results have shown that both patients carry an increased number of large ROH segments, 18 (P1 and P2) versus 5 from their mother, with a total ROH size of 76 MB (P1) and 48 MB (P2) respectively, underlying a possible recent consanguinity (Fig. 2b) [8]. Exome data were also analyzed for variants in genes associated with hypertrophic cardiomyopathy, but no potentially causative variants were detected.

Here, we describe two siblings with clinical presentation comprising progressive spasticity, motor neuropathy, ataxia, and optic atrophy, resembling Behr syndrome, and with the additional clinical finding of hypertrophic cardiomyopathy. Whole exome sequencing identified a novel homozygous deletion of three nucleotides in UCHL1. Paternal data were not available to perform complete segregation studies and confirm his carrier status. However, normal CGH array results excluded a large chromosomal rearrangement in the paternal allele, and although a deletion in UCHL1 cannot be discarded, the possible recent consanguinity identified by ROH analyses support the homozygous status assumption. Ubiquitin C‐terminal hydrolase‐L1 (UCHL1) is critically important in maintaining free ubiquitin levels through the addition or removal of ubiquitin to poly-ubiquitin chains, and thus has a central role in cytoplasmic protein degradation [10]. It is one of the most abundant proteins in the nervous system, being highly expressed in both the central and peripheral nervous system [11‐13]. Through its close interaction with the neuronal cytoskeleton, UCHL1 is thought to have important roles in axonal repair after injury, axonal transport, and synaptic function [14‐16].

Mutations in UCHL1 have been described in three families with autosomal recessive spastic paraplegia (SPG79) [3‐5]. The phenotype of the patients in the present study had many similarities to the previously reported cases (Table 1). In all cases described to date, the first symptom was of childhood-onset visual loss due to optic atrophy. The subsequent disease course was characterized by varying degrees of spasticity and cerebellar ataxia. Additional, less consistently described features include epilepsy, cognitive impairment, facial myokymia, fasciculations, and reduced peripheral sensation, reflecting the widespread expression of UCHL1 in most neuronal cells. The clinical presentation of our patients and all previously reported cases were compatible with Behr syndrome (Table 1).

First described by Carl Behr in 1909, the classical Behr syndrome (MIM 210000) comprises childhood-onset optic atrophy combined with various neurological symptoms including spastic paraparesis, ataxia, mild ophthalmoparesis, peripheral neuropathy, and a variable degree of learning difficulties [17]. While the optic atrophy in these patients remains stable, other neurological signs progress during childhood becoming more prominent in the second or third decades [17].

Autosomal recessive OPA3 mutations have been identified in Iraqi Jewish patients presenting with Behr syndrome and 3-methylglutaconic aciduria (Costeff syndrome) [18] and more recently autosomal dominant [19] and recessive [20] OPA1 mutations were shown in Behr syndrome without metabolic abnormalities. We reported six patients with Behr syndrome and autosomal recessive mutation in C12orf65 [21], and a homozygous C12orf19 mutation has also been reported to cause this phenotype [22], illustrating further genetic heterogeneity of this phenotype. All previously reported genetic forms of Behr syndrome affect mitochondrial proteins involved in different mitochondrial functions. The detection of UCHL1 mutations in this phenotype adds another molecular mechanism, protein de-ubiquitination contributing to Behr syndrome and raising the possibility that this gene is also contributing to mitochondrial protein quality control.

In contrast to previously described cases, however, the siblings in this study both presented with the additional clinical feature of hypertrophic cardiomyopathy. Specifically, both patients demonstrated globally hypertrophied left ventricles in the absence of acquired causes of ventricular dysfunction (e.g., hypertension, myocardial ischaemia, valve dysfunction, prior exposure to toxins, and environmental pathogens). In addition, detailed family history failed to identify other family members known or suspected to be affected by a myocardial disease. The tissue distribution of UCHL1 is predominantly within the nervous system, although it is also expressed at low levels in gonadal cells [23]. Interestingly, UCHL1 is also upregulated in other cells under specialized conditions, for example in fibroblasts during wound healing and in pancreatic, colorectal, medullary thyroid, and breast cancer cells [24‐27]. In these conditions, it is suggested that deregulation of the ubiquitin–proteasome system (UPS) may lead to uncontrolled cell growth. Furthermore, the UPS plays a key role in maintaining protein homeostasis and cardiac function, and UCHL1 has been shown to play a key role in this regulation. Knockdown of UCHL1 in cardiomyocytes and mouse hearts rescued cardiac hypertrophy induced by agonist or pressure overload, and overexpression resulted in the opposite effect [28]. We have not carried out functional studies of mutated UCHL1 protein (p.Gly210del). The Glycine residue at position 210 is close to the C-terminus, which regulates protein aggregation and stability [29]. The removal of the final four amino acids from the C-terminus renders the protein insoluble and abolishes binding to ubiquitin substrates [30]. Glycine at position 210 is located just upstream of the final beta-sheet and may have an impact on protein folding and stability. Further studies will be required to ascertain how the c.627_629del; p.(Gly210del) UCHL1 mutation might lead to clinical hypertrophic cardiomyopathy. We recognize that it is not possible to completely exclude an alternative genetic or acquired cause for hypertrophic cardiomyopathy in these siblings, or an unrecognized cardiac disease in previous family members. Nonetheless, the presentation in these cases raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations. The sudden cardiac death in both patients highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.