Table 4 Histories of patient with possible abnormal CNS findings

Patient 1: At age 24 y, patient 1 had normal intelligence and no signs of neurological abnormalities. However, in an MRI at 20 y, signal from gray substance appeared well differentiated in first “echo” from the T2 sequences, but was inverted in the second echo, principally in peripheral regions. There was also a heterogeneous hyposignal from the posterior part of the central gray nuclei.

4: At age 11 y patient 4 attended normal school, but developed severe headaches. Nystagmus, dysdiadochokinesis and increased tendon reflexes were found. An MRI showed delayed myelination in all but the internal capsule and brainstem. On AdoMet supplementation symptoms and signs completely resolved and MRI showed restoration of normal myelination

Patient 5: At age 14 y this patient was considered slow relative to the rest of her family and to have learning disability. At age 7.5 years she had, on the Wechsler Intelligence Scale for Children-Revised, a verbal score of 88 and a performance score of 84. An MRI at age 13 y was normal, including normal myelination.

Patient 7: Patient 7 was on methionine restriction between 1 month and 4 months, and again from 6 months to 9 months. An MRI at that time was normal and a normal diet was restarted. Early gross motor milestones were delayed. Although neurologically normal at age 4 y, an MRI showed diffusely abnormal white matter and patchy basal ganglia bilaterally and abnormally high signal in the inferior aspect and inferior midbrain. At age 7 y the boy was in special class with memory and learning disabilities. MRI was stable at age 14 y. A short trial of AdoMet was stopped by the family because they did not notice improvement in clinical status. At age 17.8 years there was notable impaired function and a fine tremor.

Patient 8: At age 7 y this girl had tremor and increased tone in her right arm with dystonia and dysmetria. An MRI at 9 y showed decreased T1 signal and increased proton density in the left posterior putamen abutting the posterior limb of the internal capsule. At age 11 y, myelination was arrested to about 1½ year level.

Patient 9: At age 6 y patient 9 had learning disability. On a Stanford-Binet Intelligence test he scored 65 (1^st percentile), but an MRI was entirely normal.

Patient 13: An MRI of this girl at 8 y showed patchy alterations of white matter. At age 16 she required extra time to complete high-school tasks and was given an “Individualized Education Program”.

Patient 20: An MRI at age 10 y showed white matter changes.

Patient 22: At age 2.8 y patient 22 had febrile seizures with clonic jerks of the right arm and bilateral clonic seizures. An MRI showed myelination arrest in the central white matter, putamen, and globus pallidus. An MRI at 4.7 y showed delayed myelination, and supplemental AdoMet was started. At age 5.4 y her score on an intelligence test improved to 69. An MRI at 6.4 y showed normal myelination.

Patient 29: As early as age 2 y this boy was suspected to have mild mental retardation. At age 12 y he started to have concentration difficulties in school and his performance worsened. At age 13 y full scale IQ was 73 (3.6 percentile) and an MRI showed normal gray-white matter differentiation in T1 weighted sequence and overall mild hyperintensity of the subcortical white matter in T2 weighted sequence, suspicious of hypomyelinization.

Patient 30: From age 3 weeks patient 30 was on dietary methionine restriction and betaine supplementation. He was neurologically unremarkable with an IQ of 121 at age 3.5 y, but an MRI at 3.8 y showed diffuse T1 and T2 prolongation in the subcortical areas extending to deep white matter, with relative sparing of the corticospinal tracts, corpus callosum, optic radiations, ventral brain stem, and cerebellar white matter. There were symmetric lesions in the dorsal brain stem from the red nucleus to the olivary nucleus areas. Methionine restriction and betaine were discontinued at age 4 y, and at age 5 y MRI findings improved, although patchy foci of T1 and T2 shortening were still observed in the white matter [37]. At age 7 y the delay of myelination had disappeared [41].

Patient 31: This sib of #30 was on dietary methionine restriction from age 3 months to 1.8 years. An MRI at 0.8 y showed delayed myelination of white matter with T1 and T2 prolongation in the symmetric tegmental tract. At 3 y his development was normal and neurological examination unremarkable, but MRI showed delayed myelination in white matter with symmetric lesions in the dorsal brain stem [41].

Patient 32: Patient 32 was on methionine restriction from an early age. An MRI at 5 y showed delayed myelination equivalent to that in normal children’s at age 6 months. Methionine restriction was discontinued. An MRI at age 5.5 y was unchanged [36]. At age 9.4 y his IQ was 108, physical and neurological examinations were normal, but myelination was the same as that at 5.5 y.

Patient 34: This child of consanguineous parents had a large head, facial dysmorphia, severely retarded, slow and infrequent movements of the body, head and eyes with suspected central visual impairment. After start of methionine restriction and AdoMet supplementation at about 5.5 months of age, he was said by age 8.3 months to have improved, but details are not available.

Patient 35: An MRI, performed at age at 1.2 y because MAT I/III deficiency with severe hypermethioninemia had been established, showed bilaterally symmetrical restricted diffusion in the commissural fibers of the corpus callosum, anterior commissure, internal capsule, and globus pallidus. Spectroscopy demonstrated a diminished NAA peak. MRI at 1.8 y after 6 months of AdoMet administration, showed improvement in areas of restricted diffusion in the corpus callosum, anterior commissure, globi pallid, and white matter. The right anterior commissure was the only area where restricted diffusion was possibly slightly increased.

Patient 36. This identical twin of patient 37, was born prematurely at 32 weeks gestation. At age 2.3 y each twin had developmental delays, especially of speech, but an MRI of brain of one twin was normal.

Patient 37: See identical twin, patient 36.

Patient 38: This daughter of consanguineous parents and sib of patient 39 was noted at age 3 y to have developmental delay. At age 5 y she had myoclonic epilepsy treated with valproic acid. At age 11.1 y she was perfectly healthy apart from learning difficulties for which she was in a special class at grade 2 level. At age 12.8 y she was in 4^th grade rather than 7^th. An MRI showed prolonged relaxation time and shortened apparent diffusion coefficient

Patient 39: An MRI at 5.2 y showed: prolonged relaxation time, and 2shortened apparent diffusion coefficient in this boy. At age 10.5 years he was in 3^rd grade rather than 5^th, but otherwise well.

Patient 41: An MRI at 0.24 y showed: abnormal symmetric T2 hyperintensity along the cortical spinal tract from the perirolandic white matter through the centrum semiovale, post limb internal capsule, cerebral peduncles, anterior pons and medulla. Also present were symmetric abnormal signal within the dorsal brainstem tegmental tract, extending into the cerebellum and along the hippocampal formations and within the fornix. Within these areas there was restricted diffusion and diffuse swelling. The patient was started on methionine restriction which has continued to present. AdoMet supplementation was started at age 6.7 y. An MRI at 7.1 y was normal and the parents think AdoMet has been very helpful.

Patient 42: An MRI of this boy at 1.2 y showed bilateral symmetrical areas of hyperintense T2-weighted images in white matter at the level of temporal-insular and temporal-mesial, deep parietal, ponto-mesencephalic, dorsal and cerebral peduncles with involvement of the structures above and the capsular lenticular corpus callosum. ADC values were reduced to diffusion. At age 1.5 y he was noted to have speech delay.

Patient 43: This boy was on methionine restriction from age 0.8–3.2 y. At 3.3 y a neuropsychological evaluation found a developmental age of 27 months and IQ’s of 78 on performance and 57 on reasoning. The diet was restarted. An MRI at 3.8 y showed delayed myelination peripherally throughout. On FLAIR examination there were multiple periventricular focal white matter hyperintensities.

Patient 45: At age 4 y physical and neurological examinations and physiotherapeutic testing of patient 45 were normal, but an MRI showed white matter changes and delayed myelination. At age 4.1 y she started protein restriction and supplemental AdoMet. At age 4.5 y physical and neurological examinations and physiotherapeutic testing continued to be normal. An MRI showed normal white matter and delayed myelination.

Patient 46: This woman was on methionine restriction from age 0.1–4.0 y, then on a normal diet. Her IQ by WISC-R at age 9 y was 99 [15, 46]. An MRI at age 30 y showed T1 and T2 prolongation in the deep white matter, but physical and mental development have been entirely normal.

Patient 47: A dietary history is not available for this patient. At age 9 y she had dysdiadochokinesia and MRI showed hypomyelination. At age 10 she had normal cognition and an MRI at age 17 y was almost normal.

Patient 50: An MRI of patient 50 at 4.3 y showed: white matter changes, in particular restricted diffusion in the area of the genu of the corpus callosum. There were no changes in T1 or T2. Supplementation with AdoMet, 200 mg/d was started at age 4.4 y and the dose increased to 400 mg/d at 4.5 y. The patient’s behavior with regard to aggression and hyperactivity were improved at 4.9 y.

Patient 51: The behavior of this younger sister of patient 50 deteriorated by age 3.7 y and supplementation with AdoMet was started at 200 mg/d. Outcome not know to date.

Patient 56: This woman was ascertained and genotyped at age 38 y as a result of having given birth to two children with transient hypermethioninemia on newborn screening. She had never been on methionine restriction. She received average grades throughout school and has an associate degree. She has had hand tremors since childhood and is affected with depression. Physical examination showed increased deep tendon reflexes, tremors, dysmetria and dysdiadochokinesis.

Patient 60: Despite her normal development until age 1.4 y, an MRI showed extensive abnormal signal in the white matter of the corpus callosum and of the anterior commissure. Neuroimaging at age 2 years showed similar results [40]. At age 5.6 years she showed possible mild neuropsychotic delay and hyperreflexia.

Patient 61: At early age (3 weeks) this boy was treated with methionine restriction and betaine because of mild hyperhomocysteinemia. At age 2.5 years pyridoxine was added. Treatment was discontinued at age 3.9 years. Brain demyelination was revealed at age 3.5 years and confirmed at 4.5 years. At age 5.5 no neurological symptoms were reported.

Patient 62: At age 2.1 years developmental delay and autistic action of this boy led to the start of dietary methionine restriction. An MRI at age 2.3 y was normal and the diet was discontinued at age 2.4 y. IQ is 108 at age 3.3 y. At age 4.3 y the boy was developing normally and attending kindergarten.

Patient 63: At age 10 months an MRI of patient 63 showed diffuse abnormal lesions in the white matter indicative of delayed myelination. T2-weighted images showed no myelination in the external capsules or anterior limbs of the internal capsules, but lack of T1-weighted images made evaluation difficult. At 18 months the abnormal lesions in the white matter were more extensive. However, at age 2.9 y, there were no neurological signs.