Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride.

We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake.

Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide.

BACKGROUND: Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. OBJECTIVE: We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. RESULTS: 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. CONCLUSION: AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing.

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex 1 deficiency.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G>A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.