The causes of elevated transaminases are many, spanning from transient, harmless conditions to ones associated with a progressive, life-threatening course [
1]. Here we present three patients with TMEM199-CDG, a recently described genetic cause of hypertransaminasemia [
2]. They all carried the same set of compound heterozygote mutations, despite no known common family ancestors. One of the mutations, c.92G > C, was previously reported by Jansen et al. [
2], whereas the other one is pathogenic due to its early frameshift/termination. Using Western Blot analysis in patient fibroblasts, it was shown that there is no measurable amount of TMEM199 protein, indicating that the missense mutation causes a diminished production or a rapid degradation of the resulting protein. A protein product from the c.13-14delTT allele would not be picked up by the antibody used in the Western Blot, however, given its early termination, we think it is very unlikely that such a protein would be functional at al. The clinical and biochemical findings in our patients were consistent with the previously published cases, and included, apart from hypertransaminasemia, deficient TF glycosylation and low ceruloplasmin, slightly increased copper content of the liver, mild non-progressive liver fibrosis and normal (except one patient [
2]) psychomotor development. The only patient that has been diagnosed with symptoms from the nervous system, including benign hypotonia and psychomotor developmental issues [
2], has a homozygous mutation (c.92G > C) in
TMEM199, which could indicate consanguinity and thus a possible second mutation as a cause of these symptoms. Notably, the clinical course for two of these patients has been stable over two decades, with no deterioration of the liver pathology or development of other symptoms. TMEM199 is the human orthologue of yeast Vma12p, which acts as a chaperone in the formation of the V-ATPase, the proton pump responsible for the acidification of the vesicles of the secretory pathway [
3]. Why TMEM199-CDG mainly presents with hepatopathy is enigmatic. Mutations in a number of genes involved in the formation of the V-ATPase (either encoding subunits or assembly factors) cause a plethora of symptoms with either systemic or organ specific features [
11‐
15]. In several of these disorders, pathological TF glycosylation (Type 2 patterns) is detected, as in patients with mutations in
ATP6V0A2 (OMIM 219200) [
14],
ATP6V1A (OMIM 617403) and
ATP6V1E1 (OMIM 617402) [
15],
ATP6AP1 (OMIM 300972) [
13] and
CCDC115 (OMIM 616828) [
11]. This was also the case in our patients as well as in the four previously published TMEM199-CDG patients [
2]. The glycosylation pattern indicates a Golgi related problem (CDG-II) stressing the need for a tight pH regulation in the Golgi stacks for proper function of the glycosylation enzymes. Disturbances in copper metabolism in patients with CDG-II [
16] as well as in V-ATPase deficiencies [
11,
13,
15] have been reported. These include hepatopathy with low serum ceruloplasmin and low serum copper. In both TMEM199-CDG and CCDC115-CDG, a modest accumulation of copper in the liver is also seen (this report and [
11]. The mechanisms behind these disturbances are at the moment unclear, but potentially involve at least partial loss of either or both of the copper transporting proteins ATP7A and ATP7B. In Wilson’s disease (ATP7B deficiency) [
17], export of copper from the hepatocyte (and neuron) is deficient. This causes low serum ceruloplasmin, low serum copper but accumulation of copper in the liver, similar to the TMEM199-/CCDC115-CDG patients. However, ATP7B is not glycosylated [
18] and its transfer of copper is not pH dependent [
19], why a potential link between V-ATPase malfunction and loss of ATP7B mediated copper transportation might thus reside in the synthesis or degradation of the ATP7B protein. This has not yet been investigated. In the case of ATP7A related disorders (Menkes disease or occipital horn syndrome), the uptake of intestinal copper is deficient, leading to low serum copper, low ceruloplasmin but also low copper in liver tissue [
20]. ATP7A is, in contrast to ATP7B, glycosylated [
18] and deficient glycosylation could potentially affect its function. Also, a very recent study showed that several COG subunits (involved in Golgi homeostasis and glycosylation) are within the interactome of ATP7B, linking Golgi homeostasis, glycosylation and intracellular copper homeostasis [
21]. The patients with TMEM199-CDG described so far have displayed a strikingly similar clinical presentation, with hepatic features resembling other V-ATPase chaperone deficiency syndromes, however without associated symptoms such as hypogammaglobulinemia [
13], epilepsy and cognitive impairment [
11,
13] noted in the related syndromes.