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Berardinelli–Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive disorder characterised by near-complete absence of adipose tissue since birth or early infancy.1 Affected individuals have acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hypertriglycaemia and altered glucose tolerance or diabetes mellitus. 1-Acyl-glycerol phosphate acyltransferase 2 (AGPAT2) and seipin gene were identified as candidate genes of congenital generalised lipodystrophy.2 3
The neurological manifestations in patients with seipin mutations are variable, including silver syndrome, variants of Charcot–Marie–Tooth disease type 2, distal hereditary motor neuropathy type V, spastic paraplegia and mental retardation.2 3 4 5 Herein we report a patient with congenital lipodystrophy who carries a novel compound heterozygous mutation in the seipin gene and presented with dystonia, mental retardation and behaviour change.
A 28-year-old man was admitted to the hospital because of progressive gait disturbance for several years. On examination, he had a distinctive appearance of hollow cheeks, apparent muscular hypertrophy, acromegaloid features of face, palms and soles, acanthosis nigricans of axilla and groin, abundant curly scalp hairs and generalised subcutaneous fat loss. In addition, there were torticollis, abnormal posturing of the fingers when the limbs were outstretched, axial dystonia and an abnormal thigh abduction and foot dystonia (in particular inturning of right foot) when he was walking. The dystonic posture was more severe during action than resting. The rest of neurological examination was unremarkable. He had been treated with trihexyphenidyl and baclofen to relieve the dytonia but was ineffective.
Abnormal fasting blood glucose (186 mg/dl), glycosylated haemoglobin (6.6%) and triglyceride (317 mg/dl) were found. Abdominal sonography demonstrated moderate fatty liver and splenomegaly. Skin biopsy from his left cheek showed mild dermal fibrosis and almost complete absence of subcutaneous fat. These results confirm the diagnosis of lipodystrophy.
Brain magnetic resonance imaging was unremarkable. Neuropsychological assessment revealed a mild mental retardation and impairments of temporal orientation, core linguistic function, memory, visual perception of angles and directions, constructional praxis, executive function and manual dexterity of both hands. The patient also had some behavioural changes such as stealing female underwear. His two elder sisters presented similar clinical features and both died of liver cirrhosis around 30 years old. The man’s parents were non-consanguineous Taiwanese.
After obtaining informed consent from all participants, genomic DNA were isolated and screened for AGPAT2 and seipin genes by polymerase chain reaction (PCR) amplification followed by direct sequencing. The gene survey did not reveal mutations of AGPAT2, and none of the published mutations in the coding region of seipin was detected. However, a novel nonsense mutation, a heterozygous G-to-T mutation at nucleotide 565 in exon 6, was identified (G565T). This mutation predicts the substitution of glutamine at codon 189 by the stop codon (E189X) (fig 1A). In addition, a heterozygous frameshift mutation was identified in exon 8, 783insG. (fig 1B). This heterozygous G insertion would lead to the truncation of seipin.
We further evaluated the presence of G565T nucleotide transition in exon 6 and frameshift mutation in exon 8 in the family members. We totally screened 37 members of this family. The mutant allele, G565T, was found in the patient’s father and 10 family members from the paternal side. The frameshift mutation in exon 8 was found in the patient’s mother and five family members from the maternal side. All family members, except this proband, with the seipin gene mutation were heterozygous and did not show BSCL phenotypes.
This patient had typical clinical presentations of BSCL earlier in the course. Later he developed dystonia and behaviour changes. There were no other members in this family having dystonia, which made familial idiopathic torsion dystonia unlikely. This patient did not have a head trauma history and was not exposed to neuroleptics or antimetics. Wilson disease was not likely because of normal ceruroplasmin and cupper level. Other clinical manifestations of some metabolic disorders such as GM1 or GM2 gangliosidosis and metachromatic leucodystrophy were not present in this case. Base on the above reasons, we suppose that dystonia may be a rare manifestation of BSCL.
Seipin/BSCL2 encodes a 398-amino-acid protein and is predicted to be a transmembrane protein located in the endoplasmic reticulum (ER). It is highly expressed in the brain and testis.5 Ito and Suzuki reported that overexpressed mutant seipin was highly polyubiquitinated and degraded by the proteasome.6 They also demonstrated that inappropriate glycosylation of mutatnt seipin exacerbates their misfolding in ER. Growing evidence indicates that many neurodegenerative diseases may have common pathological mechanisms, including dysfunction of protein quality-control system and ER stress, which lead to protein misfolding, aggregation and accumulation resulting in neuronal dysfunction in certain brain area.
Our patient carries two abnormal alleles which bear novel mutations, one frameshift mutation and one transition mutation. This result reveals that BSCL caused by the E189X and truncated of seipin is inherited as an autosomal recessive fashion. The plausible mechanism for the two mutations causing dystonia in our patient is speculated through the impaired ER stress. However, there is still a mystery as to why there were various different clinical features within seipin mutant carriers. Are there any other unknown modifier genes or environment factors contributing to the diverse presentations, or is the pathogenesis caused by heterozygous or compound heterozygous and homozygous mutation? To our knowledge, this is the first genetic proven BSCL case in Taiwan. Our patient is unusual in that he has novel compound heterozygous mutations in the seipin gene and has generalised dystonia. We conclude that BSCL with seipin gene mutation is distributed worldwide, and BSCL should be considered as a differential diagnosis of dystonia.
Competing interests None.
Patient consent Obtained.
YRW and SIH contributed equally.