(32) The Long Road to Diagnosis: MMDS6 Multiple Mitochondrial Dysfunctions Syndrome 6 Hidden Behind Familial VCP Multisystem Proteinopathy 1 for over Two Decades

Background: Multiple mitochondrial dysfunctions syndrome 6 (MMDS6) is a rare, autosomal recessive neurodegenerative disorder with onset in early childhood. In contrast to PMPCB, mutations in VCP are associated with an autosomal dominant adult-onset progressive disease known as multisystem proteinopathy 1 (MPS1), which presents clinically with inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS).

Objectives: This case report presents a 23-year-old female patient with biallelic pathogenic variants in PMPCB and a co-occurring pathogenic variant in VCP. She was misdiagnosed with early onset VCP-related neurodegenerative disorder for over 20 years. After several genetic evaluations as a young child with only a familial VCP pathogenic variant identified, her condition remained inconclusive until age 23, when updated genomic sequencing conferred a diagnosis of MMDS6.

Design/Methods: The phenotype of this 23-year-old female patient with pathogenic PMPCB variants was compared to the phenotypes seen in the previous six documented cases of MMDS6 (Table 1). The patient shares several common features, notably microcephaly, cerebellar atrophy, and developmental regression.

The patient’s VCP variant conferred a diagnosis of inclusion body myopathy with Paget’s disease of bone and/or FTD 1 (IBMPFD1). The phenotype of the 23-year-old female patient was compared to other cases of IBMPFD1 and FTD and/or ALS 6 (FTDALS6), which shares some overlapping features with IBMPFD1 since it also involves a pathogenic VCP variant (Table 2). The patient shares several symptoms with both disorders, notably limb-girdle myopathy, FTD, spasticity, and respiratory failure.

Results: The 23-year-old female patient’s childhood onset of symptoms is consistent with the pathology of MMDS6. In contrast, IBMPFD1 patients’ symptoms develop in their late 30s or older, so it is possible this patient may start showing more pathognomonic symptoms later in life. Furthermore, the patient’s early-onset mitochondrial dysfunction could lead to a more rapid onset of the pathophysiological changes seen in IBMPFD1 possibly culminating a more severe presentation of this adult onset condition.

Conclusions: This case is the first to describe the clinical manifestations of possessing pathogenic variants in both the PMPCB and VCP genes. The patient’s family has been able to make well-informed decisions about their own health care and family planning following this diagnosis. Finally, this case highlights the importance of genetic testing and offers opportunity for targeted therapies now and in the future for this patient.