Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC)

Abstract

The clbC form of methylmalonic acidaemia is a rare and poorly understood condition which results from impaired biosynthesis of methylcobalamin and adenosylcobalamin. The consequent functional deficiencies of methylmalonyl-CoA mutase and methionine synthase produce both methylmalonic aciduria and homocystinuria. Systemic symptoms and neurological decompensation comprise the clinical phenotype. In an effort to clarify the phenotype and prognosis, we obtained clinical information on 50 patients with methylmalonic acidaemia whose cells had been assigned to the cblC complementation group. We identified two distinct phenotypes; they differed in age of onset, presence of systemic symptoms, type of neurological symptoms, and outcome after diagnosis and treatment. Forty-four patients presented in the first year of life. Feeding difficulties, neurological dysfunction (hypotonia, seizures, developmental delay), and ophthalmological and haematological abnormalities characterized their clinical picture. About one-quarter of those patients died. Survival was associated with neurological impairment; only one infant was neurologically intact at follow-up. Onset in childhood, in contrast, was associated with less severe haematological abnormalities, largely involving the red cell series. Extrapyramidal signs, dementia, delirium or psychosis characterized the neurological findings. Survival, with mild to moderate disability in some, was typical in patients with later onset. Treatment in both groups included hydroxycobalamin, betaine and carnitine; complete normalization of biochemical parameters was rare.

Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management

“…The wide range of types and age of presentation (Table 1) (Mitchell et al 1986; Rosenblatt et al 1997; Shinnar and Singer 1984; Augoustides-Savvopoulou et al 1999; Roze et al 2003; Ben-Omran et al 2007; Thauvin-Robinet et al 2008), make the diagnosis of cblC disease a challenging one. The diagnosis can also be complicated by the history of normal newborn screening (Chace et al 2001), and the absence of metabolic acidosis and other systemic disturbances that would prompt the consultation by a metabolic disease specialist (Harding et al 2003).…”

“…These developmental complications include intrauterine growth retardation (IUGR) (Frattini et al 2010; Robb et al 1984; Bartholomew et al 1988; Smith and Bodamer 2002; Nogueira et al 2008) mild dysmorphic features (long facies, flat philtrum and large low-set ears), (Cerone et al 1999), microcephaly (Francis et al 2004; Smith et al 2006; Rosenblatt et al 1997; Andersson et al 1999), congenital heart disease (Profitlich et al 2009b; Andersson et al 1999) and fetal dilated cardiomyopathy De Bie et al (2009).…”

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

“…Early diagnosis and treatment can improve outcomes but cannot prevent all complications of CblC disease (Rosenblatt et al 1997;Andersson et al 1999;Boxer et al 2005;Smith et al 2006;Thauvin-Robinet et al 2007;Martinelli et al 2011;Aleman et al 2014). Early therapy may be particularly beneficial for late-onset patients, as it can be started prior to the development of any organ damage .…”

“…Early-onset patients usually present in the first months of life and have an unfavorable prognosis (CarrilloCarrasco et al 2011). Late-onset CblC patients usually present with extrapyramidal and neuropsychiatric symptoms in any decade of life (Rosenblatt et al 1997). Lateonset patients are less likely to have ocular involvement (Gerth et al 2008).…”

A Treatable Metabolic Cause of Encephalopathy: Cobalamin C Deficiency in an 8-Year-Old Male

“…2,5 Early-onset deficiency includes in utero changes and symptom onset in infants or toddlers. In utero complications of cblC include microcephaly and restricted growth.…”