3.2. SLC25A46-related PCH and Leigh syndrome

A recent study reported the identification of SLC25A46 loss-of-function mutations in four patients from two unrelated families with a diagnosis of severe congenital PCH, leading to very early mortality [22]. Then, two independent groups reported an additional seven patients from three unrelated families with severe PCH associated with truncating mutations of SLC25A46 (Table 1) [24, 25].

PCH is a rare, heterogeneous group of prenatal onset neurodegenerative disorders, mainly (but not exclusively) affecting the cerebellum and pons. The current PCH classification scheme includes 10 distinct PCH subtypes defined by clinical features and genetic etiology. PCH1 is distinguished from the other PCH subtypes by its association with spinal muscular atrophy due to spinal motoneuron degeneration; it often leads to early death. All patients with obvious loss-of-function SLC25A46 genotypes in the literature suffered severe lethal congenital PCH, presenting with the phenotypic hallmarks of cerebellar and brainstem degeneration as well as spinal muscular atrophy, respiratory failure, early death, occasional optic nerve atrophy, and axonal neuropathy. Based on these features, SLC25A46-associated PCH could be classified as PCH1, and perhaps a new PCH1 subtype, PCH1D, clinically distinguished from other PCH1 subtypes (mutations in VRK1, EXOSC3, and EXOSC8 are associated with PCH1A, PCH1B, and PCH1C, respectively) [25]. However, the most severe clinical presentation associated with SLC25A46 mutations is probably not restricted to PCH. A homozygous SLC25A46 mutation that resulted in the complete absence of the protein was identified recently in a terminally ill child with progressive brain lesions consistent with those seen in Leigh syndrome (Table 1) [20].

Cerebellar and brainstem atrophy are shared phenotypic features of PCH, Leigh syndrome, and most variant SLC25A46-related HMSN6B cases. Meanwhile, optic nerve and peripheral nerve axonal pathology are seen consistently in HMSN6B. Features that are prominent in lateronset cases might be overlooked or not assessed in neonatally lethal cases. Thus, SLC25A46 related PCH or Leigh syndrome could be extreme forms of HMSN6B.

To sum up, SLC25A46-related neurological disease has high clinical heterogeneity. Patients with biallelic SLC25A46 mutations show high phenotypic variability with respect to age of onset, clinical features, and disease course. The severity of presentation even varies between siblings. The phenotype spectrum ranges from severe disease at birth with early death to manifestation in late childhood with survival beyond 50 years of age.
