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Introduction
Mutations in the HSJ1 (Heat-Shock Protein J1) gene, also called DNAJB2 (DnaJ (Hsp40) homologue, subfamily B, member 2), have been recently described as a cause of hereditary neuropathies. The HSJ1 c.352+1G>A mutation in homozygote state has been reported as the causative mutation in a single family with autosomal recessive distal hereditary motor neuropathy (dHMN).1 Since then, two other families with different HSJ1 mutations have been described: one with a dHMN phenotype and the other with a Charcot-Marie-Tooth disease type 2 (CMT2) phenotype.2
We identified the HSJ1 c.352+1G>A mutation in 10 patients who underwent long-lasting follow-up. We describe their phenotype and clinical evolution.
Patients and methods
Ten patients from five different Spanish families had been diagnosed with dHMN or CMT2 at two tertiary referral centres in Spain between 1976 and 2014. They all underwent neurological examination and electrophysiological studies using standard techniques.3 Regular follow-up was performed in all cases and repeated electrophysiological studies were carried out in some patients.
All the families carried the HSJ1 c.352+1G>A homozygote pathogenic sequence variation. Family 1 was diagnosed by exome sequencing. Families 2 and 4 were diagnosed using a gene panel for genetic testing of CMT and dHMN. Families 3 and 5 were identified by mutational screening of the HSJ1 c.352+1G>A change, carried out in 52 patients from our registry, with autosomal recessive dHMN or CMT2, who still had no molecular diagnosis. In all cases, mutation was confirmed by Sanger sequencing and a segregation analysis was performed whenever possible.
All the patients and relatives included in the present study signed informed consent. The research protocols were approved by the respective institutional boards of the Ethics Committee of both hospitals.
Results
Pedigree information is illustrated in online supplementary figure S1. Only one of our families had known consanguinity. It was remarkable that three of the families (families 1, 2 and 5) originated from the same town.
Supplementary figures
Clinical data are summarised in table 1.
Clinical features of patients with the HSJ-1 c.352+1G>A mutation
Age of onset ranged between 8 and 31 years (median 17.50). The first reported symptoms were weakness and atrophy of the distal lower limbs, which spread insidiously to the proximal muscles. Only three patients (F1/III-1, F3/II-5 and F5/II-4) had altered sensation at the first clinical assessment. After a median follow-up of 20.50±13.25 years (range 2–44) after the symptoms first appeared, all the patients developed sensory symptoms and only the two youngest patients still presented clinical pure motor impairment. The patients with a longer disease course developed weakness in their upper limbs, which always occurred when there was severe weakness of the lower limbs. The most severely affected patients were the oldest (F3/II-5, F3/II-7 and F5/II-4). They developed dysarthria, dysphagia, facial weakness and impairment of respiratory muscles, and required assisted ventilation and percutaneous endoscopic gastrostomy placement for feeding. Patients F3/II-7 and F5/II-4 died at ages 61 and 69 years, respectively. In the last 4 years of their life, only their eye movements were preserved. In patient F5/II-4, behavioural changes with disinhibition, apathy and poor language production were noted when he was 63 years of age, when muscular atrophy was already severe. Brain MRI showed mainly right frontotemporal brain atrophy (see online supplementary figure S2). Patient F1/III-1 developed left-sided Parkinsonian symptoms at the age of 40 years. Brain single-photon emission CT (SPECT) imaging with DatSCAN showed reduced radiotracer uptake in the right striatum and the patient was diagnosed with young-onset Parkinson's disease (YOPD). The exome sequencing results showed that he carried three single nucleotide polymorphisms (SNPs) in genes related to Parkinson's disease. However, none of these three variants cosegregated with disease in his family (data not shown).
The initial electrophysiological findings for all our patients were chronic and acute denervation in the distal muscles of the lower limbs, and reduced compound motor axon potentials (CMAPs) in peripheral nerves of the lower limbs. CMAPs were relatively preserved in the upper limbs and conduction velocities fell within the normal limits. By means of the initial available electrophysiological studies, four patients were diagnosed with dHMN (F1/III-3, F2/III-3, F2/III-5 and III-6), while six patients were diagnosed with CMT2 (F1 III-1, F2/III-1, F3/II-5, F3 II/7, F4 III-1 and F5/II-4) at the time of the first assessment. In two patients (F1/III-3 and F2/III-3) with normal initial sensory responses, repeated nerve conduction studies showed abnormal sensory responses (see online supplementary table 1). Repeated electrophysiological studies revealed spreading denervation, first to the proximal muscles of the lower limbs, and then to the muscles of the upper limbs. The CMAPs in the upper limbs tended to decrease.
Supplementary table
Discussion
In this study, we found that the HSJ1 c.352+1G>A mutation manifests as dHMN and CMT2, and that some cases with an initial dHMN phenotype evolve into a CMT2 phenotype.
In our patients, the first symptom was distal muscle weakness in the lower limbs, which later spread to the proximal muscles, but with no initial sensory symptoms. After several years of follow-up, two of our patients who were initially diagnosed with dHMN developed clinical and electrophysiological sensory impairment, which started in the lower limb nerves. Currently, only two of our patients have a dHMN phenotype, they are the youngest, with shorter disease evolution. These findings lead us to believe that clinical and electrophysiological pure motor impairment occurs during the early disease course. Then, as the disease progresses, sensory disturbances in the lower limbs become apparent.
In the patients subjected to the longest follow-up time (>30 years after symptoms onset), muscle involvement had spread following a caudocranial pattern. The late disease stage evokes the final amyotrophic lateral sclerosis (ALS) stage.
HSJ1 is a member of the HSP40/DNAJ co-chaperone family. Previous studies have presented in vitro data to show that HSJ1 prevented aggregation of a SOD1 mutant protein, which is related to ALS,1 as well as of a Parkin mutant protein associated with Parkinson's disease.4 One of our patients developed YOPD and another developed frontotemporal dementia. While preparing this paper, Parkinsonism and cerebellar ataxia has been described in a Brazilian family with the HSJ1 c.352+1G>A mutation.5 All these facts could suggest that the HSJ1 protein plays a protective role in neuronal groups of the central nervous system. However, these findings may be co-incidental, so functional studies or larger case series are needed to support this hypothesis.
Acknowledgments
The authors thank the patients for having collaborated with this study. They are grateful to Itziar Llopis for sample management and Marisa Barreiro for technical assistance.
Footnotes
Contributors MF designed the study, participated in clinical data acquisition and interpretation, and wrote and edited the manuscript. MJC participated in electrophysiological studies and interpretation. JJV participated in clinical data acquisition and interpretation, and critically revised the manuscript. CM-I participated in clinical data acquisition and interpretation. FP critically revised the manuscript. JFV-C participated in clinical data acquisition. VL participated in genetic analysis and interpretation. CE participated in genetic analysis and interpretation. TS designed and supervised the study, participated in clinical data acquisition and interpretation, and critically revised the manuscript.
Funding This collaborative joint project is awarded by IRDiRC and funded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y Fomento de la Investigación within the framework of the National R+D+I Plan (grants number IR11/TREAT-CMT to TS, CM-I, FP and CE; PI12/0946 to TS), the Fundación para la Investigación del Hospital Universitari La Fe (2015/0085, PI TS). The Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative of the ISCIII. MF received a grant by Instituto de Investigación La Fe (2015/0085, PI TS). CM-I is funded by an IRDiRC grant (IR11/TREAT-CMT). FP is funded by an IRDiRC grant (IR11/TREAT-CMT). JFV-C is funded by an Instituto de Investigación La Fe grant (2013/0332). CE is funded by grants from the ISCIII (CPII14/00002 and PI12/00453) and IRDiRC (IR11/TREAT-CMT). CE has a ‘Miguel Servet’ contract funded by the ISCIII and the Research Centre Príncipe Felipe (CIPF). TS is funded by grants from the ISCIII and IRDiRC (IR11/TREAT-CMT and PI12/0946).
Competing interests None declared.
Ethics approval Institutional Review Board of the Ethics Committee of the Hospital Universitari I Politècnic La Fe and the Institutional Review Board of the Ethics Committee of the Hospital Universitario Virgen del Rocío.
Provenance and peer review Not commissioned; externally peer reviewed.