Report of Two Never Treated Adult Sisters with Aromatic l-Amino Acid Decarboxylase Deficiency: A Portrait of the Natural History of the Disease or an Expanding Phenotype?

Abstract

Two sisters were diagnosed in their adulthood with aromatic L-amino acid decarboxylase (AADC) deficiency (OMIM#608643). They experienced early myasthenia-like manifestations, myoclonic jerks, oculogyric crises, tremors, and developmental delay during childhood; clinical stabilization afterwards; and spontaneous improvement during adolescence and young adulthood. Two novel pathogenic mutations on DDC gene [p.Tyr37Thrfs*5 (c.105delC) and p.F237S (c.710 T>C)] were associated with undetectable enzyme activity in plasma and only a mild reduction of biogenic amines in cerebrospinal fluid (CSF). The increase of both 3-O-methyldopa and 5-hydroxytryptophan on CSF was the most relevant biochemical alteration denoting AADC defect in these subjects. Transdermal rotigotine remarkably improved their gross motor functions and the asthenic status they complained. The present cases broaden the phenotypic spectrum of AADC deficiency and suggest that (1) AADC defect is not a progressive neurological disease and behaves rather as a neurodevelopmental disorder that improves during the second decade of life; (2) treatment-naïve adults can still respond well to neurotransmitter therapy; and (3) the possibility of a mild presentation of AADC deficiency should be considered when examining young adults with asthenic and parkinsonian symptoms.

The Spectrum of Early Movement Disorders in Congenital Defects of Biogenic Amine Metabolism

“…49,50 Clinical observations in two of our female patients (►Table 2, patients 25 and 26) with mild symptoms evidenced that a spontaneous improvement of motor symptoms occurs during the transition from the early stages of life into adolescence and young adulthood. 54 A previously presumed minor responsiveness of motor symptoms to pharmacologic treatment in females has not been supported by following reports. 54…”

“…49 Following observations have expanded the phenotype of movement disorders in AADC deficiency to brady/akinetic and asthenic patterns that during the first year of life may mimic myasthenia condition. [51][52][53][54][55] Hypotonia can be associated with easily elicitable dystonic reactions after external stimuli. 50 In some patients, dystonic postures can be followed by a startle myoclonus.…”

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

“…An atypical postural/rest tremor may be observed during the first 2 to 4 months of life in patients with TH and sepiapterin reductase deficiencies (Video S6). A severe hypotonic‐hypokinetic presentation mimicking a neuromuscular disease may occur in AADC and TH defects . Less frequent neurological symptoms are epileptic seizures, sleep disturbance, irritability, dysarthria, increased startle, poor eye fixation, ptosis, miosis, and temperature instability.…”

“…A severe hypotonic-hypokinetic presentation mimicking a neuromuscular disease may occur in AADC and TH defects. 83,84 Less frequent neurological symptoms are epileptic seizures, sleep disturbance, irritability, dysarthria, increased startle, poor eye fixation, ptosis, miosis, and temperature instability. Common nonneurologic symptoms are short stature, nasal congestion, excessive drooling, stridor, diarrhea, constipation, feeding difficulties, gastroesophageal reflux, and hypoglycemia.…”

Successful Pregnancy in a Patient with L‐Amino Acid Decarboxylase Deficiency: Therapeutic Management and Clinical Outcome

“…We report on the successful pregnancy in a previously reported 26‐year‐old AADC patient with a mild phenotype (Table ) . Since the diagnosis at the age of 22, treatment with rotigotine, pyridoxine, and escitalopram resulted in a remarkable improvement of fluctuating muscular weakness, oculogyric crises, palpebral ptosis, balance, and gait . After, as consequence of behavioral disinhibition and reduced control of sexual impulses, rotigotine was replaced by a prolonged release formulation of pramipexole (up to 0.78 mg/day once a day).…”