PEBEL2 is a rare genetic multi-systemic disorder with a spectrum of severity. There does not appear to be a gender bias.
In the majority of cases children with PEBEL2 are born healthy and develop normally. There are rare cases of stillbirth.
Disease onset in most instances is triggered by a period of illness, fever, stress or injury in childhood or in some cases, trauma. There is one reported adult-onset case whose decline was triggered after head injury.
The majority of PEBEL2 cases reported to date have a rapid neurological decline. However, as more cases are identified, there is growing evidence that the location of the pathogenic variant in the NAXD gene could influence the clinical presentation, which may depend on the subcellular compartment that is most impacted by the deficiency of the NAXD enzyme.
Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2. This leads to the generation of two forms of the protein from a major transcript of the NAXD gene: cytoplasmic (Cyto NAXD) and mitochondrial (Mito NAXD). In addition, there is evidence of endoplasmic reticulum localisation of NAXD, giving another NAXD transcript that can be generated by alternative splicing and encoding a signal peptide.
Combined Cyto + Mito NAXD
PEBEL2 individuals with NAXD pathogenic variants that affect both the cytosolic and mitochondrial isoforms lead to the most common molecular phenotype reported to date. These individuals generally present with:
• neurological defects which may include:
o neurological regression
o progressive generalised cerebral atrophy
o bilateral basal ganglia abnormalities, with cytotoxic oedema of the basal ganglia suggestive of a mitochondrial disorder
o generalised asymmetrical cortical atrophy in the temporal and frontal lobes
o oedema or atrophy of the cerebellum
o paraspinal muscle oedema
o grey matter abnormalities in the cervical cord
• seizures
• skin lesions that are inflamed with blisters and burn-like or rash-like appearance in areas of high-skin friction or movement such as neck, chin, groin, buttocks, fingers and axillae.
The majority of these cases are fatal.
Mito NAXD
Individuals with NAXD pathogenic variants exclusively affecting the mitochondrial isoform appear to have a different clinical presentation, however, this has only recently been reported and there are only a handful of cases reported to date. Generally, these individuals present with:
• cardiac presentation including
o tachycardia
o dilated or hypertrophic cardiomyopathy
o impaired ventricular function
o acute myocarditis
• moderate motor neuropathy
• myopathy / muscle weakness
These individuals generally don’t present with the characteristic skin lesions, seizures or neurological degeneration of the ‘cytosolic + mitochondrial’ NAXD form.
They may have a more slowly progressing and less aggressive disease.
Other features of PEBEL2 during the acute clinical phase may include:
• Movement abnormalities including unsteady gait, dystonia and ataxia.
• Lethargy
• Hypotonia
• Elevated creatine kinase levels.
• Elevated lactate in cerebrospinal fluid or plasma.
• Anaemia.
• Mitochondrial respiratory chain enzymatic defects.