Clinical and Laboratory Study of Methylmalonic Acidemia

Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid
metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with
cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications
such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal
failure, growth impairment, osteoporosis, and developmental delay. The frequency of these
complications and their precipitants remain undefined. Furthermore, current treatment
protocol outcomes have continued to demonstrate substantial morbidity and mortality in the
patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been
used to treat patients. Disordered transport and intracellular metabolism of vitamin B12
produces a distinct group of disorders that feature methylmalonic acidemia as well as
(hyper)homocysteinemia. These conditions are named after the corresponding cellular
complementation class (cblC, cblD, cblF, cblJ and cblX) and are also heterogenous, clinically
and biochemically. The genetic disorders underlying cblE and cblG feature an isolated
impairment of the activity of methionine synthase, a critical enzyme involved in the
conversion of homocysteine to methionine and these disorders feature

(hyper)homocysteinemia. Lastly, a group of patients who have increased methylmalonic acid
and/or homocysteine in the blood caused by urine or by mutation(s)in recently identified
(ACSF3) and unknown genes.

In this protocol, we will clinically evaluate patients with methymalonic acidemia and
cobalamin metabolic defects. Routine inpatient admissions will last 4-5 days and involve
urine collection, blood drawing, ophthalmological examination, radiological procedures,
MRI/MRS, skin biopsies in some, and developmental testing. In a subset of patients who have
or will receive renal, hepato- or hepato-renal transplants or have an unusual variant or
clinical course and have MMA, a lumbar puncture to examine CSF metabolites will be performed.
In this small group of patients, CSF metabolite monitoring may be used to adjust therapy.

The study objectives will be to further delineate the spectrum of phenotypes associated with
these enzymopathies, query for genotype/enzymatic/phenotype correlations and search for new
genes in rare families that have evidence for an unknown class of methylmalonic acidemia
and/or homocysteinemia. The population will consist of patients previously evaluated at NIH,
physician referrals, and families directed to the study from clinicaltrials.gov as well as
the Organic Acidemia Association. Most patients will be evaluated only at the NIH Clinical
Center. However, if the NIH team decides that a patient under the age of 2 years is a
candidate subject for this research protocol, that patient may enroll at the Children s
National Medical Center (CNMC) site, pending approval by Dr Chapman, the Principal
Investigator of the CNMC location. Outcome measures will largely be descriptive and encompass
correlations between clinical, biochemical and molecular parameters.

- INCLUSION CRITERIA:

Patients of any gender, ethnicity, and age over 2 years of age with methylmalonic acidemia
and cobalamin disorder are eligible to enroll in this protocol at the NIH Clinical Center.
Affected individuals under the age of 2 years may be evaluated at Children s National
Medical Center (CNMC) as part of an evolving agreement in the Translational Program in
Pediatrics, if they are deemed eligible for participation by the NIH team and the CNMC
team. Patients will be diagnosed based on a determination of MMA and homocysteine levels in
plasma and urine. Most will have their complementation class known or pending. Molecular
genetic analyses to determine mutations will be expected to have been performed prior to
acceptance into the study. Some patients who have not yet had this laboratory test will be
admitted to the protocol based upon metabolic parameters and clinical history. This latter
category of patients might include individuals with a suspected genetic but unknown type of
MMA.

EXCLUSION CRITERIA:

The PI/AI may decline to enroll a patient for reasons such as being medically unstable,
residing in a hospital, sub-optimal metabolic control or for any concerns arising after
review of the laboratory and clinical data; any patient who requires dialysis once or
more/week and weighs <40 kg, any patient who is being treated for an intercurrent infection
with antibiotics or has evidence of an acute infection and has metabolic symptoms, any
patient who does not have a regular/local metabolic, genetic or endocrine physician and/or
a family physician, pediatrician, or internist, and any patient who may be metabolically
unstable but not acutely ill; and any patient or family who may not be able to institute
recommendations for appropriate testing and care before visiting the NIH. Each family may
be contacted by the NIH team one week prior to a pending inpatient admission to confirm
that the patient is metabolically stable and ready to visit the NIH in a state of relative
health, with an adequate supply of special formulas, medications, supplements, and if
needed, medical equipment such as feeding pumps and replacement parts for feeding tubes. A
subset of participants will be enrolled in the tissue collection part of the study only
(i.e. if they are too sick to travel).

Pregnant women may be eligible to enroll in the study if they are affected with
methylmalonic acidemia or a cobalamin disorder or are family members of an affected
subject. Pregnant women are not excluded because it is important to learn more about the
effects of this disorders in pregnant participants. This research involves no more than
minimal risk to the fetus. Affected subjects who are pregnant or become pregnant during
their participation on the study will not be withdrawn, but will be excluded from some
procedures until the pregnancy is concluded. Affected subjects who are pregnant may undergo
procedures as part of their clinical care, including

blood draws, genetic studies, and consultations, according to the clinical judgement of the
clinical team. Pregnant participants will be excluded from some procedures such as stable
isotope, GFR testing, DEXA, X-rays and MRI until the pregnancy is concluded.

Patients with methylmalonic acidemia or cobalamin disorders of any age, gender and
ethnicity, undergoing a transplantation surgery at Children s Hospital of Pittsburgh, are
eligible to participate in the tissue collection arm of the study. Pregnant women will be
excluded from tissue collection at the Children s Hospital of Pittsburgh.

For the healthy volunteers, eligibility criteria include individuals that are age 18 and
over. Exclusion criteria include: women who are pregnant, individuals being treated with
antibiotics, individuals with kidney or liver disease, individuals on a special diet such
as a high protein diet or taking protein supplements and individuals with severe
claustrophobia or other anxiety disorders.