Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists

Abstract

Background: Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomocysteinemia, methylmalonic aciduria and low plasma methionine. Despite being a well-recognized disease for pediatricians, there is scarce awareness of its adult presentation. A thorough analysis and discussion of cobalamin C defect presentation in adult patients has never been extensively performed. This article reviews the published data and adds a new case of the latest onset of symptoms ever described for the disease.

Results: We present the emblematic case of a 45-year-old male, describing the diagnostic odyssey he ventured through to get to the appropriate treatment and molecular diagnosis. Furthermore, available clinical, biochemical and molecular data from 22 reports on cases and case series were collected, resulting in 45 adult-onset CblC cases, including our own. We describe the onset of the disease in adulthood, encompassing neurological, psychiatric, renal, ophthalmic and thromboembolic symptoms. In all cases treatment with intramuscular hydroxycobalamin was effective in reversing symptoms. From a molecular point of view adult patients are usually compound heterozygous carriers of a truncating and a non-truncating variant in the MMACHC gene.

Conclusion: Adult onset CblC disease is a rare disorder whose diagnosis can be delayed due to poor awareness regarding its presenting insidious symptoms and biochemical hallmarks. To avoid misdiagnosis, we suggest that adult onset CblC deficiency is acknowledged as a separate entity from pediatric late onset cases, and that the disease is considered in the differential diagnosis in adult patients with atypical hemolytic uremic syndromes and/or slow unexplained decline in renal function and/or idiopathic neuropathies, spinal cord degenerations, ataxias and/or recurrent thrombosis and/or visual field defects, maculopathy and optic disc atrophy. Plasma homocysteine measurement should be the first line for differential diagnosis when the disease is suspected. To further aid diagnosis, it is important that genes belonging to the intracellular cobalamin pathway are included within gene panels routinely tested for atypical hemolytic uremic syndrome and chronic kidney disorders.

Keywords: Adult-onset; CblC; Cobalamin C deficiency; Homocysteine; Methylmalonic aciduria and homocystinuria; Neuropsychiatric presentation; Renal function decline; aHUS.

Fig. 1

Schematic representation of cobalamin metabolism. Dietary vitamin B12 (Cbl) is bound by intrinsic factor (IF) in the stomach, the vitamin B12-instrinsic factor complex is absorbed by enterocytes in the ileum through the cubam receptor, formed by cubilin (CUBN) and amnionless (AMN). Cobalamin is then transferred onto transcobalamin 2 (TCN2) and transported in the bloodstream. The transcobalamin 2-cobalamin complex is taken up by hepatocytes through the TC2 receptor (CD230) and transferred to lysosomes, from which it is released by the membrane-bound transport proteins LMBD1 and ABCD4 and processed by MMACHC (whose transcription is controlled by HCFC1). MMADHC binds to MMACHC and then processed cobalamin is either directed towards Methylcobalamin (MeCbl) synthesis through methionine synthase reductase (MTRR) or to the mitochondrion, where Adenosylcobalamin (AdoCbl) is synthetized thanks to MMAA and MMAB proteins. MeCbl is a cofactor for the enzyme methionine synthase (MTR), involved in remethylation from homocysteine to methionine, while AdoCbl is a cofactor of methylmalonyl-CoA mutase (MMUT), which catalyzes the transformation of L-Methylmalonyl-CoA (MMA-CoA) into Succynil-CoA, which can then be used in the Krebs cycle [2]

Fig. 2

Case report storyline. Timeline of clinical events from the onset of arterial hypertension to the diagnosis of methylmalonic aciduria and homocystinuria, CblC type of the reported case of adult-onset CblC disease. ER, Emergency Room; aHUS, atypical Hemolytic Uremic Syndrome, OH-cobalamin, Hydroxycobalamin

Fig. 3

Renal biopsy. Optical microscopy (a, b) and electron microscopy (c–e) of the reported case of adult-onset CblC disease. a The glomerular basement membranes are diffusely slightly thickened and show extensive double contours or collapse (PAS, original magnification × 400). b pseudothrombi are occasionally observed in glomerular capillary lumens (AFOG, original magnification × 400). c the glomerulus shows extensive duplication of basement membranes (“multilayering” aspect) associated with subendothelial expansion, endothelial swelling and loss of normal fenestration (chronic microangiopathic damage; original magnification × 5200). d, e Electron dense deposits with a vaguely structured annular or microtubular appearance are evident in the basement membranes (mainly subendothelial and intramembranous) and in the mesangium (original magnification × 15,500 in d and e)

Fig. 4

Brain MRI. In the T2-weighted sequences, foci of altered hyperintense signal of the bilateral fronto-temporo-parieto-occipital subcortical white matter are evident (white arrows)

Fig. 5

Brain biopsy. Hematoxylin–eosin image shows an increase in the cell density of the white matter and the presence of macrophages (a) and Luxol fast blue staining highlighting the presence of foci of demyelination (b)

Fig. 6

Frequency of clinical signs and symptoms in adult-onset patients. Incidence of overall symptoms with disease progression: the X-axis shows the percentage of symptoms, while Y-axis lists the symptoms of CblC disease

Fig. 7

Patients’ cohort genotype. MMACHC gene structure and coding pathogenic variants reported in association with adult-onset CblC disease. The non-truncating variants are shown in the upper part of the figure, while the truncating ones are showed in the lower part. The three splicing variants c.81 + 1G > A, c.82-1G > A and c.82-12_82-9delTTTC are not represented in the figure, but they all mapped into the intron 1 of the gene. The size of character of the variants is proportional to the frequency of their occurrence in the cohort. Known protein domains are indicated in light blue. The two new variants found in our patients are highlighted by arrows