Adenylosuccinate lyase (ADSL, EC 4.3.2.2) deficiency

A recent survey conducted by the CDC has demonstrated that autism spectrum disorders may be more common in the United States than previously believed. Although the exact causes of the disease remain to be fully understood, studies have revealed that nearly 20 specific genetic diseases manifest with autism features. We believe that it is essential to distinguish those patients affected with genetic diseases manifesting with autism features from other autism patients, as there are significant differences in diagnosis and treatments. Our recent research work on ADSL deficiency (OMIM 103050) is a typical example of our approach to these genetic disorders.

ADSL catalyzes two distinct reactions in de novo purine biosynthesis. In patients with ADSL deficiency, succinyladenosine (SA) and succinylamino-imidazolecarboxamide riboside (SAICAr), two intermediates of the pathway, are accumulated in their bodies. Our laboratory in DDC Clinic has established a convenient filter paper method for ADSL deficiency screening based on the Bratton-Marshall test with urine samples. Working with Drs. Baochuan Guo and Aimin Zhou  of Cleveland State University, we have developed a mass spectroscopy method for further assessment of SA and SAICAr as biomarkers in patient’s urine samples. Our ongoing collaborations include the development of a more practical and economical laboratory approach to screen, diagnose and further assess ADSL deficiency, and the development a cellular model for the design of therapeutic strategies for autism caused by ADSL deficiency.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is one of the most common genetic cardiac diseases affecting 1 of every 500 people. The disease, genetically inherited in an autosomal dominant with incomplete penetrance pattern, has a broad spectrum of clinical manifestations from a benign asymptomatic course to a malignant course with serious arrhythmias, heart failure, and sudden cardiac death.

In an effort to find the cause of a severe neonatal hypertrophic cardiomyopathy in our community, we have performed a genome-wide mapping in three affected infants in collaboration with Dr. Erik Puffenberger of The Clinic for Special Children and Dr. J.R. Bockoven of Akron Children’s Hospital. A novel homozygous mutation, c.3330+2T>G, has been identified in the splice-donor site of intron 30 in MYBPC3, a previously identified cardiomyopathy related gene. The mutation resulted in skipping of the 140-bp exon 30, which led to a frame shift and premature stop codon in exon 31 (p.Asp1064GlyfsX38). To review the publication, click here.

While we are working on further understanding the pathology of both homozygosity and heterzygosity of this particular mutation, we believe that it is equally important to develop some evidence-based practical strategies to deliver medical services to those heterozygous carrier of c.3330+2T>G mutation who often do not have health insurance. In fact, this group of people represents a unique cohort who carries the same hypertrophic cardiomyopathy causative mutation, which will limit, to some degree, other genetic variations, and simplify our research work in many different ways. Therefore, our further work through this unique cohort may have a broad application and benefit many other affected individuals since the ultimate pathological mechanism and molecular bases of hypertrophic cardiomyopathy are fairly analogous regardless of the underlining etiologies.


Microcephalic osteodysplastic primordial dwarfism
(MOPD) type I

DDC Clinic has our first infant patient with MOPD, commonly known as ‘Beachy disease’. Genetically, the disease is autosomal recessive.

At birth, children with this disease are very small (weighing 1-3 pounds even though full term). Sometimes they do not grow well after birth. They have very small heads without any hair, eyebrows, or eyelashes. Their eyes appear large in their small face and their ears are very small and in an unusual position. Ridges on the skull may be very noticeable and the limbs are usually short. Dislocated hips and elbows are common in these babies, thus, they may have trouble moving their wrists, hips, knees or ankles. These children also have underdeveloped brains and significant developmental delays.

The gene mutation responsible for this disease is unknown and we are working with Dr. Judy Westman and Dr. Albert de la Chappelle at Ohio State University in Columbus.


Prolidase Deficiency Update

Since finding the first child with prolidase deficiency in our community, we have been working with another research group – Dr. Hal Scofield’s team at the Oklahoma Medical Research Foundation.

Dr. Scofield developed a new method to measure prolidase activity using a matrix-assisted laser desorption ionization time of flight mass spectrometry. Using this method, we can distinguish normal, heterozygotes and homozygotes for prolidase deficiency. The test has been successfully used in the cord blood samples of several high-risk newborns and led to the diagnosis in on of our patients soon after birth. A publication is in press in Analytic Biochemistry. DDC Clinic is co-author.

To date, a total of five patients have been identified in our geograpical area. The genealogy analysis of these patients leads to the common ascendants back to the seventh generation. Direct sequencing of PCR amplified genomic DNA from the patients revealed the same mutation in each patient.

This novel mutation, resulted in an arginine being replaced by a premature stop-codon at amino acid residue 265 of prolidase, a 493-amino acid protein. All patients had undetectable, or nearly undetectable, serum prolidase activity, which might explain why the prolidase deficiency in our patients is so severe.

Our research with our collaborators will continue to be focused on potential effective treatment of the disease, including anti-oxidants and cord blood stem cell transplants.

To read the Prolidase assay, please click here.


PKU Update

In general, the tolerance to dietary phenylalanine largely relies on how much activity of phenylalanine hydroxylase in patients’ body system, which is usually determined by type of gene mutations (over 400 mutations have been described in the medical literature). However, in our practice, we have found some PKU patients have significantly better dietary phenylalanine tolerance than their PKU siblings. If we assume the PKU siblings share the same gene mutation and have similar enzyme levels, then we have to ask why they have different dietary phenylalanine tolerance? This recently launched pilot study funded by MACPAD is an approach to this question aimed at identifying some “protective” factors - genetic, biochemical or environmental - in those PKU individuals having better dietary phenylalanine tolerance.

Progress: Eleven patients from three families have expressed an interest in or are already enrolled in the study. Interestingly, after we constructed an extensive family tree based on our genealogical information, we have found that all these patients can be tracked back to one married couple, if we go back 6 to 7 generations. This so-called “founder” effect is a common phenomenon in some small isolated communities. Working closely with Drs. Morton and Puffenberger at The Clinic for Special Children in Lancaster, the mutation of the IVS10-11 G>A has been identified. In fact, this is one of the common mutations in PKU patients in Europe. We suspect that all of our patients have this type of mutation. We are currently in the process of collecting samples from all the study participants to confirm the mutation. If indeed all participants have the same mutation as we hypothesize, we will move into next stage of the study to search for other potential “protective” factors.