Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected. Symptoms and signs
The clinical phenotypes of CMAMMA are highly heterogeneous and range from asymptomatic, mild to severe symptoms. The underlying pathophysiology is not yet understood. The following symptoms are reported in the literature:

metabolic acidosis
coma
hypoglycemia
seizures
gastrointestinal disease
developmental delay
speech delay
failure to thrive
psychiatric disease
memory problems
cognitive decline
encephalopathy
cardiomyopathy
dysmorphic featuresWhen the first symptoms appear in childhood, they are more likely to be intermediary metabolic disorders, whereas in adults they are usually neurological symptoms. Causes
CMAMMA can be divided by causation into two separate inherited disorders: one is a deficiency of the mitochondrial enzyme acyl-CoA synthetase family member 3, encoded by the ACSF3 gene (OMIM#614265); the other disorder is a malonyl-CoA decarboxylase deficiency encoded by the MLYCD gene (OMIM#248360). ACSF3 deficiency
CMAMMA due to ACSF3 is inherited in an autosomal recessive manner. The ACSF3 gene is located on chromosome 16 locus q24.3 and consists of 11 exons and encodes a 576-amino-acid protein. CMAMMA can be caused by homozygous or compound heterozygous variants in the ACSF3 gene. Based on minor allele frequency (MAF), a population incidence of ~ 1: 30 000 can be predicted for CMAMMA due to ACSF3.
Nonbacterial thrombotic endocarditis (NBTE) is a form of endocarditis in which small sterile vegetations are deposited on the valve leaflets. Formerly known as marantic endocarditis, which comes from the Greek marantikos, meaning "wasting away". The term "marantic endocarditis" is still sometimes used to emphasize the association with a wasting state such as cancer. Risk factors
Marantic vegetations are often associated with previous rheumatic fever. Other risk factors include:
hypercoagulable states
malignant cancers, especially mucin-producing adenocarcinomas (most commonly associated with pancreatic adenocarcinomas)
systemic lupus erythematosus: Referred to as Libman-Sacks endocarditis
trauma (e.g., catheters)

Valve predilection
The disease affects the valves with following predilection: mitral valve > aortic valve > tricuspid valve > pulmonary valve

Histopathology
Grossly, vegetations form along lines of valve closure and are generally symmetric with a smooth or verrucoid (warty) texture. Histologically, lesions are composed of fibrin (eosinophilic) and platelets but, unlike bacterial etiologies, contain little evidence of PMNs, microorganisms or inflammation. Diagnosis
Due to the non-invasive nature of NBTE, clinical examination may or may not reveal a new murmur. An embolic stroke may be the first feature to suggest diagnosis of NBTE. An echocardiograph may be used to further assess for valvular lesions. References


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