Kimberly A. Chapman

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100-000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.

Natural history of propionic acidemia.

Propionic acidemia is an organic acidemia that can lead to metabolic acidosis, coma and death, if not treated appropriately in the acute setting. Recent advancements in treatment have allowed patients with propionic acidemia to live beyond the neonatal period and acute presentation. The natural history of the disease is just beginning to be elucidated as individuals reach older ages. Recent studies have identified the genomic mutations in the genes PCCA and PCCB. However, as of yet no clear genotype-phenotype correlations are known. As patients age, the natural progression of propionic acidemia illuminates intellectual difficulties, increased risk for neurological complications, including stroke-like episodes, cardiac complications, and gastrointestinal difficulties, as well as a number of other complications. This article reviews the available literature for the natural history of propionic acidemia.

Acute management of propionic acidemia.

Propionic acidemia or aciduria is an intoxication-type disorder of organic metabolism. Patients deteriorate in times of increased metabolic demand and subsequent catabolism. Metabolic decompensation can manifest with lethargy, vomiting, coma and death if not appropriately treated. On January 28-30, 2011 in Washington, D.C., Childrens National Medical Center hosted a group of clinicians, scientists and parental group representatives to design recommendations for acute management of individuals with propionic acidemia. Although many of the recommendations are geared toward the previously undiagnosed neonate, the recommendations for a severely metabolically decompensated individual are applicable to any known patient as well. Initial management is critical for prevention of morbidity and mortality. The following manuscript provides recommendations for initial treatment and evaluation, a discussion of issues concerning transport to a metabolic center (if patient presents to a non-metabolic center), acceleration of management and preparation for discharge.

Chronic management and health supervision of individuals with propionic acidemia

Propionic acidemia is a relatively rare inborn error of metabolism. Individuals with propionic acidemia often have life-threatening episodes of hyperammonemia and metabolic acidosis, as well as intellectual disability. There are many reports of additional problems, including poor growth, stroke-like episodes of the basal ganglia, seizures, cardiomyopathy, long QTc syndrome, immune defects, pancreatitis and optic neuropathy; however, there is little information about the incidence of these problems in this rare disease. Additionally, there are no clear guidelines for medical or surgical management of individuals with propionic acidemia. Through a comprehensive and systematic review of the current medical literature and survey of expert opinion, we have developed practice guidelines for the chronic management of individuals with propionic acidemia, including dietary therapy, use of medications, laboratory monitoring, chronic health supervision, use of gastrostomy tubes and liver transplantation.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

BackgroundThe disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood.AimsTo evaluate the complex clinical phenotype of OAD and UCD patients at different ages.ResultsAcquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut0 patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population.ConclusionsNeurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

Neurologic considerations in propionic acidemia.

Propionic acidemia (PA) is an organic acidemia which has a broad range of neurological complications, including developmental delay, intellectual disability, structural abnormalities, metabolic stroke-like episodes, seizures, optic neuropathy, and cranial nerve abnormalities. As the PA consensus conference hosted by Childrens National Medical Center progressed from January 28 to 30, 2011, it became evident that neurological complications were common and a major component of morbidity, but the role of imaging and the basis for brain pathophysiology were unclear. This paper reviews the hypothesized pathophysiology, presentation and uses the best available evidence to suggest programs for treatment, imaging, and monitoring the neurological complications of PA.

Characteristic Brain Magnetic Resonance Imaging Pattern in Patients With Macrocephaly and PTEN Mutations

We describe an MRI phenotype seen in a series of patients with mutations in PTEN who have clinical features consistent with PTEN hamartoma tumor syndrome (PHTS). Retrospective review of clinical data and MRI was performed in 23 subjects evaluated in four different tertiary care centers with clinical programs in inherited disorders of the white matter. Patients were referred due to abnormal MRI features and abnormal PTEN sequencing was identified. All subjects had significant macrocephaly (on average >4 SD above the mean), developmental delay with or without autism spectrum disorder and uniform MRI features of enlarged perivascular spaces and multifocal periventricular white matter abnormalities. The phenotype of PHTS may include MRI abnormalities such as multifocal periventricular white matter abnormalities and enlarged perivascular spaces. These neuroimaging findings, in association with macrocephaly and developmental delay, should prompt consideration of PTEN as a diagnostic possibility.

Thiamine pyrophosphokinase deficiency causes a Leigh disease like phenotype in a sibling pair: Identification through whole exome sequencing and management strategies

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical course.

Propionic acidemia consensus conference summary

In January 2011, Childrens National Medical Center in Washington, D.C. hosted a consensus conference to discuss and develop recommendations for the diagnosis and management of propionic acidemia. Several resulting manuscripts from this conference are included in this issue. Topics covered include recommendations for acute management of metabolic decompensations, recommendations for chronic management and health monitoring, natural history of disease in patients with propionic acidemia, and neurologic complications in propionic acidemia.

Propionic acidemia: To liver transplant or not to liver transplant?

Propionic acidemia (PA) is an intoxication-type inborn error of metabolism caused by decreased ability of propionyl-CoA carboxylase to convert propionyl-CoA to methylmalonyl-CoA. Affected children typically present with metabolic acidosis, which can evolve to lethargy and eventual coma and death during episodes of catabolism if not adequately treated (1, 2). Recent reports have highlighted the potential for cardiac involvement in PA, especially the development of life-threatening cardiomyopathy, which might be related to abnormalities of mitochondrial function (3). Although propionyl-CoA carboxylase activity is present throughout the body, i.e., not restricted to the liver, success in treating other inborn errors of metabolism such as urea cycle defects, methylmalonic acidemia, and maple syrup urine disease with liver transplantation has made this procedure an attractive therapeutic option (4, 5). Initial attempts to treat PA by liver transplantation were predominately unsuccessful with high mortality and morbidity (6, 7). With improved surgical techniques and anti-rejection medications and protocols, more recent attempts to treat patients with PA by liver transplantation have been more successful. Many, but not all, patients are able to stop dietary measures, and there is a decrease in number and intensity of acute decompensations, improved cardiac function, and stabilization of neurologic complications. In a multi-site, retrospective study of 12 individuals with PA receiving orthotopic liver transplant (OLT), the one-yr survival rate was 72.2% and there was clear clinical improvement, including the elimination of episodes of hyperammonemia and liberalization of diet (i.e., avoidance of meats but no specific dietary restriction of protein), slowed neurological decline, and the prevention of cardiomyopathy (8). A recent report described five individuals with median follow-up of 7.3 yr; all were surviving and had good graft function; though, one had experienced a basal ganglia metabolic stroke approximately one yr after transplantation. Three received left lateral segments (one from a living carrier relative), one received a left lobe, and the other had auxiliary partial orthotopic liver transplantation. Post-transplantation development was normal in one patient, moderately impaired in another, and mildly impaired for the other three (9). Another report of three children with PA who received living-related donor grafts (from heterozygous carrier parents) documented survival for 21–59 months following surgery without further episodes of acute decompensation or metabolic acidosis (10). Kasahara and colleagues in the May issue of Pediatric Transplantation provide further evidence to support the use of liver transplantation in patients with PA, which is present in approximately one in 465 000 live births in Japan. Three children who received living donor grafts between ages seven and 26 months showed stabilization of their clinical disease in terms of neurologic and cardiac findings, and decreased episodes of metabolic acidosis. One patient did have a metabolic decompensation, which was treated using standard methods. Normal liver graft and cardiac function, as well as normal development and decreased hospitalization were also described in these children. The fact that liver transplantation does not resolve the underlying biochemical defect completely was clearly demonstrated by the persistence of pathognomonic PA metabolites in blood and urine postoperatively. In January 2011, a group of clinicians, scientists, and patient representative groups provided a number of acute and chronic health management guidelines for patients who have PA. On the basis of most recent reports of positive outcomes in liver transplantation in patients with PA, consideration of liver transplantation in individuals with recurrent episodes of hyperammonemia Pediatr Transplantation 2012: 16: 209–21