Symptoms in clinically identified patients
The first SCADD patient was originally reported by Amendt and coworkers (Amendt et al.
1987) and subsequently genetically confirmed by Naito in 1990 (Naito et al.
1990). The patient was reported to suffer from lethargy, hypertonia, and circulatory problems with metabolic acidosis during her first week of life. Although she was reported to show normal growth and development without recurrence of metabolic acidosis up to the age of 2 years, Bhala et al. later reported that this patient had died, without reporting clinical details (Bhala et al.
1995). As this publication included another SCADD patient who died after initial presentation with severe skeletal muscle hypotonia, a devastating clinical course of SCADD was suggested. However, the same publication included another two patients who initially presented with “possible hyperactivity” and “probable seizure activity” but with a normal follow-up. Initially, a few other patients with SCADD had been reported (Bhala et al.
1995; Amendt et al.
1987; Coates et al.
1988), however in these patients, the diagnosis was, to our knowledge, not genetically confirmed. As the definitive diagnosis of SCADD requires molecular testing (van Maldegem et al.
2006), these patients are excluded from this review.
Subsequently, a large cohort of SCADD patients was presented by Corydon et al., and several case reports were published (Corydon et al.
2001; Baerlocher et al.
1997; Bok et al.
2003; Birkebaek et al.
2002; Kmoch et al.
1995; Matern et al.
2001; Kurian et al.
2004). Based on these publications, SCADD appeared to be associated with a wide spectrum of clinical signs and symptoms, including developmental delay, hypotonia, epilepsy, and hypoglycemia, and in solitary cases dysmorphic features, vomiting, failure to thrive, hepatic dysfunction after premature delivery, and bilateral optic atrophy. One case report suggested the association between SCADD and acute fatty liver of pregnancy in the mother. Again, a striking spectrum was observed in patient outcome, which was reported for seven patients of whom five fully recovered, one slowly progressed, and one died (Kurian et al.
2004; Birkebaek et al.
2002; Bok et al.
2003; Matern et al.
2001; Seidel et al.
2003; Kmoch et al.
1995).
In 2006, we reported data on 31 Dutch SCADD patients (van Maldegem et al.
2006). The most frequently reported symptom in this cohort was developmental delay, followed by epilepsy, behavioral disorders, and hypoglycemia. Behavioral disorders, observed in eight out of the 31 patients, had not been previously reported in SCADD patients. Remarkably, most of the clinically severely affected patients belonged to the group of patients homozygous for the c.625G > A variant. In four patients, additional diagnoses that were highly likely to be causing the clinical symptoms were made after the initial diagnosis of SCADD.
In 2008, Tein and coworkers published a study on ten SCADD patients (Tein et al.
2008) in whom developmental delay was again the most common symptom, but this time, hypotonia was also as frequent. In addition, this study reported for the first time a relatively high prevalence of lethargy (five patients), myopathy (four patients), and facial weakness (three patients). All patients in this study were of Ashkenazi Jewish descent, carried the
c.319C > T mutation, and were either homozygous for this mutation or had the c.625G > A variant on the other allele. In two patients with myopathy, a muscle biopsy revealed multiminicore disease, a rare congenital myopathic disorder. However, other genetic causes for multiminicore disease, in particular, mutations in
SEPN1 and
RYR1, which are present in about 50% of cases (Jungbluth
2007), had not been excluded. In the same year, Pedersen and coworkers published a study on a very large cohort of 114 SCADD patients from Europe, New Zealand, and Canada. Again developmental delay was the most frequently reported clinical sign, in combination with hypotonia, seizures, and failure to thrive (Pedersen et al.
2008). In addition, several patients were reported to have failure to thrive and hypotonia without developmental delay, and a smaller group had dysmorphic features. A third study, also published this same year, by Waisbren and coworkers, reported on another six clinically identified patients (Waisbren et al.
2008). In three of them, newborn screening failed to detect SCADD, and in the other three, no screening for SCADD was performed. The most significant symptoms in these six patients were developmental delay, hypotonia, feeding problems, failure to thrive, and epilepsy.
Clinical symptoms in SCADD individuals identified by newborn screening
With the implementation of newborn screening for SCADD in the USA and Australia, the clinical spectrum of SCADD has expanded. Several follow-up studies of SCADD newborns diagnosed through newborn screening were published within the last few years. The first one reported 17 SCADD newborns who all remained symptom free at follow-up during their first 2 years of life (Rhead et al.
2002). Of the three patients reported by Koeberl et al. (
2003), one developed seizures and a cerebral infarction at the age of 10 weeks, and the other two remained symptom free during their first 3 years of life. One of the eight children reported by Waisbren and co-workers (
2008) showed developmental delay consisting of a language delay at the age of 2 years. Jethva and Ficicioglu reported a group of 14 children with SCADD, of whom 11 were identified by newborn screening and three diagnosed by screening of sibs diagnosed through newborn screening. During a follow-up of 1–7 years, in two of them (siblings), speech delay was diagnosed. A causative relationship between this speech delay and SCADD was considered unlikely, as both parents had learning disabilities, suggesting other causes (Jethva and Ficicioglu
2008). All four Australian SCADD children diagnosed by newborn screening and studied during 6 years remained symptom free. SCADD has meanwhile been excluded from the Australian screening panel because of supposed lack of clinical significance (Wilcken
2008).
An interesting finding by Waisbren and coworkers is a relatively high prevalence of pregnancy complications in mothers of children diagnosed with SCADD by newborn screening as well as in mothers of the group of SCADD patients diagnosed because of clinical symptoms (Waisbren et al.
2008). In five out of 14 patients, hypertension, maternal bradycardia, pre-eclampsia, and mild hemolysis, elevated liver enzyme levels, and a low platelet count (HELLP syndrome) were reported. This suggests that fetal SCADD, like other FAO disorders such as long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency, might be associated with pregnancy complications, as previously suggested (Matern et al.
2001). However, in almost 30% of all pregnancies in the Dutch population, mild to moderate pregnancy complications were reported, including hypertensive disorders and pre-eclampsia (Dutch Hospital Database
2009). Furthermore, the association between SCADD and maternal pregnancy complications was not detected in the Dutch cohort of SCADD patients (van Maldegem et al.
2006), as maternal disease during pregnancy was only reported in four out of 24 patients (17%) for whom pregnancy details were known (unpublished data).
Family studies
Thirty-seven relatives (20 parents and 17 sibs) of the SCADD patients from the Dutch cohort were investigated for their
ACADS genotype, and nine of them were found to have the same
ACADS genotype as the proband (van Maldegem et al.
2006) . Except for one father with an
ACADS genotype homozygous for the c.625G > A variant, all relatives with an
ACADS genotype identical to the proband were found to have increased C4-C and/or EMA. Eight relatives had always been healthy, whereas one had a history of transient food refusal during her first year of life.