The current report presents two unrelated patients with HIBM2 identified in a U.S. based specialty neuromuscular clinic. Patient 1 followed a classic presentation for HIBM2. She developed distal weakness in her early 20s that progressed to wheelchair dependence after 20 years. Now nearly 30 years after her initial symptoms she is profoundly weak in all muscle groups with the exception of her quadriceps which, although abnormal on ultrasound, still has normal (5/5) strength. Her muscle biopsy demonstrated classic histochemical features for HIBM2 with small angular fibers and rimmed vacuoles.
In contrast, patient 2 presented with several atypical features for HIBM2. He had marked respiratory weakness as measured by bedside spirometry. Unlike other inclusion body myopathies, the diaphragm and intercostals muscle are typically spared in patients with GNE
]. He developed weakness in his 6th
decade, the oldest onset of weakness reported in a patient with HIBM2. Most manifesting patients with homozygous GNE
mutations develop symptoms by the end of the 3rd
decade. Argov et al reported 5 non-manifesting patients with homozygous GNE
mutations the oldest of which was 68 [6
]. It is not known if this patient went on to develop symptoms of HIBM2. Unlike patient 1 and other patients with HIBM2, patient 2 had only minimal abnormalities on ultrasound of the rectus femoris [7
]. His muscle biopsy was also atypical for HIBM2 and revealed scattered necrosis with no obvious vacuoles. A “necrotizing myopathy” has been previously described in another a patient with homozygous GNE
mutations although a subsequent biopsy did find rimmed vacuoles [8
]. Interestingly both our patient and this previously reported patient had necrosis evident on a quadriceps biopsy. The quadriceps muscle is typically unaffected in HIBM2. Proper selection of muscle biopsy site may avoid misdiagnosis and repeat biopsies in patients with HIBM2 [9
]. Patient 2's sensory findings and their relation to GNE
mutations is unclear. Many patients with HIBM2 report parethesias or extremities that feel cold [6
], however; our patient had subject sensory complaints and nerve conduction changes that could be consistent with an axonal polyneuropathy.
Our study identified three novel GNE
mutations adding to the growing list of HIBM2 mutations. Patient 1 is a compound heterozygote with a novel A26P and A631V mutation. A missense mutation at residue 631 has been previously reported in multiple patients and families [1
]. The novel A26P mutation lies next to a previously reported P27S mutation [10
]. Patient 2 is a compound heterozygote for two novel mutations, H333R and Y361X. These mutations lie within exon 6 and 7 respectively. Interestingly a previously reported family with homozygous mutations in exon 7 (L379H) identified rimmed vacuoles in only 2/5 family members [11
] and another report of a single patient with homozygous V367I mutations in GNE
found necrosis, inflammation and rimmed vacuoles [12
]. Perhaps patients homozygous for mutations within this region have less classic HIBM2 pathology.
The vacuoles in patients with HIBM2 are thought to be autophagic in nature. This is evidenced by detailed pathologic studies of HIBM2 patient biopsies which found that hydrolytic enzyme stains such as acid phosphatase are present around and within sarcoplasmic vacuoles [13
]. Other studies have identified an increase in Lamp2 around vacuoles and within the sarcoplasm of muscle fibers from HIBM2 patients [14
]. The accumulation of the autophagic marker LC3 and its localization to vacuolar structures is seen in sporadic inclusion body myositis [15
] and inclusion body myopathy associated with paget's disease of the bone and fronto-temporal dementia [17
]. We found an increase in acid phosphatase staining as well as LC3 and Lamp2 positive immunoreactivity in both our HIBM2 patients. This staining was not exclusively localized to vacuoles but instead was found throughout the sarcoplasm of scattered fibers. This data supports a defect in the autophagosome-lysosomal system as a pathogenic mechanism in HIBM2 and further suggests that a dysregulation in autophagy may be more widespread than vacuolated fibers.
We identified these two patients based upon their phenotypic presentation of distal weakness with relative sparing of quadriceps strength. Despite this preservation of strength, the quadriceps of patients with HIBM2 can demonstrate pathology on ultrasound [7
]. Although our two, sequence confirmed, HIBM2 patients had differing presentations, one feature unifies them: a distal myopathy with relative sparing of the quadriceps strength. Patients with this distinctive pattern of weakness should be evaluated for GNE
mutations regardless of family history, time of onset, radiologic evidence of quadriceps pathology, or absence of vacuoles on muscle pathology.