Intellectual disability: A potentially treatable condition.

The application of genomics has greatly increased the diagnosis of specific monogenic causes of intellectual disability and improved our understanding of the neuronal processes that result in cognitive impairment. Meanwhile, families are building rare disease communities and seeking disease-specific treatments to change the trajectory of health and developmental outcomes for their children. To date, treatments for intellectual disability have focussed on metabolic disorders, where early treatment has improved cognition and neurodevelopmental outcomes. In this article, we discuss the treatment strategies that may be possible to change the neurodevelopmental outcome in a broader range of genetic forms of intellectual disability. These strategies include substrate modification, enzyme replacement therapy, gene therapy and molecular therapies. We argue that intellectual disability should now be considered a potentially treatable condition and a strong candidate for precision medicine.

Free urinary sialic acid levels may be elevated in patients with pneumococcal sepsis.

OBJECTIVES: Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria (GNE variants) and infantile sialic acid storage disease/Salla disease (SLC17A5 variants). Traditionally, UFSA has been measured using specific single-plex methodology in relatively small cohorts of patients with clinical symptoms suggestive of these disorders. The use of multiplex tandem mass spectrometry urine screening (UMSMS) has meant that UFSA can be measured semi-quantitatively in a much larger cohort of patients being investigated for suspected metabolic disorders. We hypothesised that the neuraminidase of Streptococcus pneumoniae may release free sialic acid from endogenous sialylated glycoconjugates and result in increased UFSA levels. METHODS: We conducted a retrospective review of clinical records of patients who were identified as having S. pneumoniae infection and who also had UMSMS at the time of their acute infection. RESULTS: We identified three cases of increased UFSA detected by UMSMS screening that were secondary to S. pneumoniae sepsis. Additional testing ruled out genetic causes of increased UFSA in the first patient. All three patients had overwhelming sepsis with multiorgan dysfunction which was fatal. Glycosylation abnormalities consistent with the removal of sialic acid were demonstrated in serum transferrin patterns in one patient. CONCLUSIONS: We have demonstrated in a retrospective cohort that elevation of UFSA levels have been observed in cases of S. pneumoniae sepsis. This expands our knowledge of UFSA as a biomarker in human disease. This research demonstrates that infection with organisms with neuraminidase activity should be considered in patients with unexplained increases in UFSA.

Galactose treatment of a PGM1 patient presenting with restrictive cardiomyopathy.

We report a patient diagnosed with PGM1-CDG at 11 years of age after two biallelic likely pathogenic variants in PGM1 were found on research genomic sequencing. To our knowledge, he is the first patient with PGM1-CDG to be reported with a restrictive cardiomyopathy. Other clinical manifestations included cleft palate, asymptomatic elevated transaminases, intellectual disability and myopathy resulting in exercise intolerance. He was trialed on oral galactose therapy in increasing doses for 18 weeks to assess if there was any biochemical and clinical benefit. His galactose was continued for a further 9 months beyond the initial galactose treatment period due to improvements in exercise tolerance and myopathy. Treatment with galactose demonstrated an improvement in liver function and myopathy with improved exercise tolerance. Treatment with galactose for 15 months did not change heart function and exercise stress test results were stable.

Smith-Lemli-Opitz syndrome: clinical and biochemical correlates.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the DHCR7 gene that result in reduced cholesterol biosynthesis. The aim of the study was to examine the biochemical and clinical features of SLOS in the context of the emerging evidence of the importance of cholesterol in morphogenesis and steroidogenesis. METHODS: We retrospectively reviewed the records of 18 patients (including four fetuses) with confirmed SLOS and documented their clinical and biochemical features. RESULTS: Seven patients had branchial arch abnormalities, including micrognathia, immune dysfunction and hypocalcemia. Thymic abnormalities were found in three fetuses. All four patients with a cholesterol level of ≤0.35 mmol/L died. They all had electrolyte abnormalities (hyperkalemia, hyponatremia, hypocalcemia), necrotizing enterocolitis, sepsis-like episodes and midline defects including the branchial and cardiac defects. Patients with cholesterol levels ≥1.7 mmol/L had milder features and were diagnosed at 9 months to 25 years of age. All 10 patients had intellectual disability. One patient was found to have a novel mutation, c.1220A>G (p.Asn407Ser). CONCLUSIONS: We suggest that screening for adrenal insufficiency and for hypoparathyroidism, hypothyroidism and immunodeficiency, should be done routinely in infants diagnosed early with SLOS. Early diagnosis and intervention to correct these biochemical consequences may decrease mortality and improve long-term outcome in these patients.