Newborn diagnosed with rare case of ALAD porphyria: Report
Whole genome sequencing led to correct diagnosis and treatment
A newborn boy with low muscle tone, and breathing and feeding problems during his first days of life was diagnosed with delta-aminolevulinic acid dehydratase (ALAD) deficiency porphyria after undergoing whole genome sequencing, according to a recent report.
This was the third reported case of infantile-onset ALAD deficiency porphyria, an extremely rare type of porphyria. The baby’s symptoms eased after red blood cell transfusions and supportive care, providing an important finding for the long-term management of the disease, researchers noted.
“This case highlights the importance of leveraging rapid whole genome sequencing for the diagnosis and minimization of devastating sequelae of exceptionally rare disorders, such as [ALAD deficiency porphyria],” they wrote.
The study, “Profound hypotonia in an infant with δ-aminolevulinic acid dehydratase deficient porphyria,” was published as a brief communication in the European Journal of Human Genetics.
Porphyrias are caused by disruptions in the production of heme, which is a molecule needed for the transport of oxygen in red blood cells. This is a stepwise process that involves multiple enzymes. When this process becomes impaired, intermediate molecules normally used to make heme build up to toxic levels, causing a variety of symptoms.
About 10 cases of ALAD porphyria reported worldwide in male patients
ALAD porphyria is a very rare type of porphyria marked by a nearly complete deficiency in an enzyme called delta-aminolevulinic acid dehydratase, or ALAD. The disease is characterized by acute attacks, usually involving abdominal pain, nausea, and constipation, as well as neurological symptoms. The disease usually causes more severe attacks than other types of acute porphyria that may occur during childhood. To date, about 10 cases of ALAD porphyria have been reported worldwide, all involving male patients.
In the report, researchers in the U.S. described the case of a newborn boy of Hispanic ethnicity, born at 39 weeks of pregnancy, who was admitted to the emergency department with generalized muscle weakness, breathing difficulties, and a hoarse cry.
He was intubated and put on mechanical ventilation for one day. Blood analysis revealed the presence of bacteria, for which he was prescribed an antibiotic. On the sixth day of life, he was transferred to a neonatal intensive care unit because of worsening muscle weakness.
Further examination revealed the boy had a weak gag reflex and lacked a suck reflex. Muscle tone, or overall muscle resistance to stretching, was absent in the arms and decreased in the legs.
Blood work revealed a mild decrease in the levels of magnesium and sodium, which were corrected by intravenous (into-the-vein) feeding. Anemia, or a low number of red blood cells or hemoglobin (the protein that transports oxygen in red blood cells), was also noted, for which he received a red blood cell transfusion.
Whole genome sequencing, which involves examining the entire DNA sequence of an individual’s genetic material, revealed he had two mutations in the ALAD gene, consistent with the diagnosis of ALAD porphyria. In agreement with this, lab tests showed he had high levels of aminolevulinic acid and total porphyrins in the urine.
At 24 days old, he required an additional red blood cell transfusion, after a sudden drop in hemoglobin levels.
Boy had normal development and growth at follow-up months later
The patient’s muscle tone and feeding gradually improved, and he was discharged at the age of 34 days. At five and six months follow-up, the boy had normal development and growth, with normal muscle tone in the limbs, although it was still decreased in his trunk muscles.
“Neurological improvement following [red blood cell] transfusion may have resulted from suppression of [red blood cell production] and less overproduction of ALA and porphyrins by the [bone] marrow,” the researchers wrote.
At six months of age, the boy experienced a significant increase in ALA levels, even though he showed no symptoms indicative of disease progression. Monitoring of urinary ALA and porphyrins was planned every six months.
Considering the limited number of cases available in the literature, the patient’s risk for developing future symptoms cannot be predicted, according to the researchers.
Eight other cases have been documented, with symptom-onset varying from birth up to the age of 63. One case previously reported was similar to the described patient, with decreased muscle tone at birth and a low breathing rate. Despite treatments, including a liver transplant, that patient died.
“Treatment protocols are tailored to individual response, and further studies are needed to determine whether treatment should target the marrow or liver,” the researchers wrote.
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