# Muscular and Molecular Pathology Associated with SPATA5 Deficiency in a Child with EHLMRS
## 2 Results
### Proteomic Profiling  
An examination of the proteomic profile performed on the muscle biopsy of the patient revealed the robust quantification of 1778 proteins (ProteomeXchange project accession #: PXD026182).  
Among these, we observed the significant up-regulation of 31 proteins and down-regulation of 51 proteins (Table S1), out of which 8, respectively 7, showed a mitochondrial localization (Table 1).  
Filtering the proteomic signature for significantly dysregulated proteins with known involvement in specific diseases (using both UniProt and OMIM) resulted in a selection of associations with a phenotypical overlap to EHLMRS, or selected features in our patient. (Table 2) Out of the 31 significantly up-regulated proteins, 4 proteins have a known disease association. They are associated with primarily muscular disorders (PURA1, LAMA2), and other diseases with muscular involvement. This includes muscular weakness and lipid storage myopathy alongside a facial dysmorphism in glutaratic academia IIB (ETFB) [13]. ECHA is known to be associated with multiple acyl-CoA dehydrogenase deficiency (MADD), myopathy, rhabdomylysis and sensorimotor axonal neuropathy in mitochondrial tritunctional protein deficiency, and recurrent mylalgia in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency [13; 14; 15; 16]. Overall, an association with fatty acid beta-oxidation, but also motor function and acetyl-CoA C-acyltransferase activity can be noted.  
Out of the 51 significantly down-regulated proteins, 15 proteins have a known disease association. They are linked to a large variety of biological processes and molecular functions, and only some display a phenotypical overlap to EHLMRS. Among these proteins, some are associated with a primarily neuromuscular disorder (TELT, HSPB8, HXK1, PRPS1) or myopathy (LDHA). Others are linked to dystonia and central nervous system disorders (SPRE), deafness or hearing loss (COX1, SMPX, PRPS1, CAH2, ACY1), encephalopathy (CMC1, VATA, ACY1), various neuro- or neuropathies (COX1, CATD, HXK1), structural central nervous system anomalies or lesions, partly with visual impairment (COX1, HXK1, PRPS1, ACY1) as well as connective tissue disorders (CO5A1, VATA) (see OMIM number for further, itemized reference). Furthermore, psychomotor retardation and muscle weakness are associated with carbonic anhydrase II deficiency (CAH2) in autosomal recessive osteeptrosis III (OPTB3) [17].  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**UniProt Entry** & **Gene Name** & **Patient vs. Control** & \(p\)**-Value** \\ \hline HMCS2\_HUMAN & _HMGCS2_ & 6.67 & 0.000 \\ SPEB\_HUMAN & _AGMAT_ & 2.46 & 0.000 \\ THIM\_HUMAN & _ACAA2_ & 2.38 & 0.000 \\ KAD3\_HUMAN & _AK3_ & 1.98 & 0.001 \\ ATPD\_HUMAN & _ATP5F1D_ & 1.98 & 0.003 \\ ETFB\_HUMAN & _ETFB_ & 1.95 & 0.000 \\ ECHA\_HUMAN & _HADHA_ & 1.91 & 0.000 \\ NDUB6\_HUMAN & _NDUFB6_ & 1.90 & 0.003 \\ COX5B\_HUMAN & _COX5B_ & 0.54 & 0.008 \\ CMC1\_HUMAN & _SLC25A12_ & 0.53 & 0.011 \\ ATP5\_HUMAN & _ATP5J_ & 0.52 & 0.009 \\ COX1\_HUMAN & _MT-CO1_ & 0.50 & 0.026 \\ KAD2\_HUMAN & _AK2_ & 0.50 & 0.008 \\ CQ10A\_HUMAN & _COQ10A_ & 0.49 & 0.034 \\ HXK1\_HUMAN & _HKI_ & 0.31 & 0.000 \\ \hline \hline \end{tabular}
\end{table}
Table 1: Dysregulated proteins within the patient’s muscle biopsy showing mitochondrial localization.  
\begin{table}
\begin{tabular}{c c c c c c} \hline
**Protein** & **Localization** & **Gene Name** & **\(p\)-Value\({}^{\circ}\)** & **Associated Disease (HOMIM)** \\ \hline PURAI\_JHMAN\({}^{1}\) & Cytoplasm & _ADSSL1_ & 0.000 & \# 6472003 MVPGATITY, DESTAL, S\_MPDS \\ \hline  & & & & \# 647085 \\  & & & & & \\  & & & & & \\  & & & & & & \\  & & & & & & \\  & & & & & & \\  & & & & & & \\  & & & & & & \\ \end{tabular}
\end{table}
Table 2: Dysregulated proteins and their associated diseases presenting with phenotypical overlap to EHIMRS.