Table 1

hree families (F1-P1/P2, F2-P1/P2/P3, F3-P1/P2) were of Arab origin,

F1-P1/P2 and F2-P1/P2/P3 have been previously published [2]

ACO2 614559 2/3 TR20* [34] Intellectual disability, truncal hypotonia, strabismus NM_001098.3:c.336C>G: p.(Ser112Arg) hom Known variant [35], pathogenic, AR

A p.Ser112Arg missense mutation was first identified in 2 families with infantile cerebellar-retinal degeneration.28 Affected individuals exhibited developmental delay including severe psychomotor retardation, with an age at onset between 2 and 6 months. Brain MRI revealed cerebellar degeneration and white matter abnormalities (dysmyelination). Optic atrophy and retinal degeneration were readily identifiable in the setting of progressively severe visual impairment. Mitochondrial aconitase enzymatic activity was significantly reduced in lymphoblasts.

athogenic variants in mitochondrial aconitase were originally described in two families of Middle Eastern descent. The resulting defects in ACO2 activity were associated with a relatively severe clinical course that included optic and cerebellar atrophy associated with hearing loss and severe to profound developmental delay (8). Subsequent to that original report (preceding the results on our patient), Metodiev et al. described an additional five subjects in three families (two consanguineous) from France and Algeria with other ACO2 pathogenic variants (9). In that cohort, although the core symptoms of ataxia, optic nerve involvement and developmental delay were again noted, the severity of the associated symptoms varied widely. Our report therefore serves to further expand the phenotype associated with ACO2 deficiency in a similar manner – our patient falls outside of the ethnic groups so far described, and did not have evidence of cerebellar atrophy on MRI or of significant optic nerve involvement at the time of evaluation. However, the aconitase activity is within the range of previously reported patient’s with infantile cerebellar-retinal degeneration syndrome, and the ACO2 protein activity is similar to at least one other patient (Figure 5).

The differential diagnosis of neurodegenerative disorders with atrophy of the cerebral and cerebellar cortex and cerebellar vermis is broad even in young age groups; concomitant occurrence of degeneration of the retina points to lysosomal storage disorders, mitochondrial disorders, defects of carbohydrate glycosylation, and infantile neuroaxonal dystrophy.1–4 We hereby report on the identification of a tricarboxylic acid (TCA) cycle defect manifesting in infancy by the degeneration of the cerebrum, cerebellum, and retina. The subjects of this study were eight individuals, two males and six females, originating from two unrelated families of Arab Muslim origin (Figure 1). Their clinical data are summarized in Table 1. All were born following an uneventful pregnancy and delivery and had normal birth weights, head circumferences, and Apgar scores. Symptoms were first noted at 2–6 months of age and included variable appearance of truncal hyptonia, head bobbing, athetosis, generalized seizures, and ophthalmologic abnormalities that included strabismus, nystagmus, abnormal eye movements, and abnormal pursuit. The course was characterized by failure to thrive, gradual evolution of severe muscle wasting despite satisfactory oral intake, worsening of the hypotonia, attenuating deep tendon reflexes until complete areflexia was reached, progressive microcephaly, variable forms of seizures that were typically triggered by intercurrent febrile illnesses and were partly responsive to anticonvulsants, and failure to gain developmental milestones, culminating in profound psychomotor retardation. A distinctive feature was the appearance of head bobbing and athetoid movements of the upper limbs along with horizontal nystagmus when the individuals were held at the upright position. Visual tracking, normal at the newborn period, steadily deteriorated with the gradual evolution of bilateral optic atrophy. Visual evoked potentials in early infancy were normal, but the electroretinogram responses became critically reduced over the first two years of life, indicating severe retinal dystrophy. Similarly, auditory brain responses declined steadily, reflecting sensorineural hearing loss of variable severity. EEG disclosed generalized or focal spike and wave activity and slow background compatible with nonspecific encephalopathy. Electrophysiologic assessment of peripheral muscles and nerves performed in individual V-2 at 2 years revealed a normal electromyogram and a mild decrease of peripheral sensory and motor velocity suggesting demyelination. Taken together with the gradual disappearance of tendon reflexes, this finding indicates an evolving peripheral demyelinating neuropathy. Figure 1. Open in a new tab Pedigrees of the Two Families (A) Family A and (B) Family B. Affected individuals are represented by filled symbols.Table 1. Clinical Features of Affected Individuals Family A Family B IV-3 IV-5 V-2 V-5 V-7 III-1 III-2 III-3 Sex m f f f m f f f Current age (years) 18 13 7 3 0.5 9 8 2 Birth weight (centile) 2,900 g (10) 3,700 g (75) 2,700 g (10) 2,800 g (15) 3,700 g (75) 3,220 g (25) 3,450 g (50) 2,750 g (10) Birth head circumference (centile) 35 cm (40) 35 cm (50) 35 cm (50) 34 cm (25) 35 cm (40) 34.5 cm (40) 35 cm (50) 34 cm (25) Initial manifestations (age at presentation) H, A (5 months) H, A (6 months) H, A (2 months) H, E (4 months) H, E (3 months) H, S (3 months) A, H (5 months) A, E (5 months) Current weight (centile) 25 kg (−5 SD) 26 kg (−4 SD) 11 kg (−5 SD) 9 kg (−4 SD) 7.7 kg (25) 13 kg (−6 SD) 12 kg (−6 SD) 8 kg (−4 SD) Current head circumference (centile) 47 cm (−5 SD) 49.5 cm (−3 SD) 46.5 cm (−3.5 SD) 46.5 cm (5) 42.7 cm (25) 48.5 cm (−2.5 SD) 48 cm (3) 45.5 cm (5) Global DD/MR profound severe profound profound moderate profound profound severe Current motor skills no intentional movements crawls, rolls sits with support does not roll rolls, does not sit lift head when supine does not role does not role roles both sides Current cognitive skills vegetative state, no smile smile, recognize family smile, recognize family smile, recognize family smile, recognize family no eye contact, does not recognize family no eye contact, responds to auditory stimuli smile, recognize family Ataxia yes yes yes yes very mild yes yes yes Seizures generalized generalized focal and generalized focal and generalized no generalized myoclonic and focal focal and generalized no Retinal dystrophy (age at diagnosis) not evaluated severe (4 years) severe (1 year) severe (1 year) not evaluated profound (2 years) profound (1.5 years) moderate (1.5 years) ophthalmology optic atrophy, strabismus optic atrophy, strabismus optic atrophy, nystagmus optic atrophy, nystagmus, strabismus strabismus optic atrophy, nystagmus optic atrophy, nystagmus optic atrophy, nystagmus, strabismus Initial MR scan (age) not done normal (11 months) mild CoA (3 months) mild CoA (frontal and temporal) (11 months) normal (in utero, 30 weeks) CoA (frontal and temporal) mild thinning of CC (7 months) CoA abnormal WM (16 months) normal (in utero, 31 weeks) Last MR scan (age) not done severe CeA, moderate CoA (frontal and temporal), abnormal periventricular WM signal (12 years) severe CeA, moderate CoA (frontal and temporal), thin CC abnormal WM signal (4 years) severe CeA, moderate CoA (frontal and temporal), thin CC, abnormal WM signal (2.5 years) not done not done mild CoA and CeA (1y) Tendon reflexes absent brisk absent absent normal absent decreased absent Other severe scoliosis moderate SNHL severe SNHL (hearing aids) Open in a new tab The following abbreviations are used: A, ataxia/athetoid movements; H, hypotonia; E, eye abnormalities; S, seizures; HC, head circumference; DD, developmental delay; MR, mental retardation; CoA, cortical atrophy; CeA, cerebellar atrophy; WM, white matter; CC, corpus callosum; SNHL, sensorineural hearing loss.During gestation and throughout the first 6 months, brain MRI was typically normal. Thereafter, repeated MR scans (Figure 2) displayed progressive cerebellar atrophy of both hemispheres and the vermis. In addition, symmetric cortical atrophy gradually evolved, affecting mainly the frontal and temporal lobes along with a striking thinning of the corpus callosum. White matter abnormalities, indicated by T2 and fluid-attenuated inversion recovery (FLAIR) periventricular hyperintense signals, were first noted during the second year of life. Taken together, these serial MR scans revealed generalized progressive brain atrophy affecting primarily the cerebellum and to a lesser extent the white matter and the frontal and parietal lobes of the cerebral cortex. Figure 2. Open in a new tab Representative MRI Findings (A) T2-weighted, coronal section image of individual V-2 at 3 months shows a normal cerebellum and mild cortical atrophy. (B) T1-weighted, coronal section scan of the same individual at 4 years displays severe atrophy of the cerebellar hemispheres (arrowheads) and the vermis (arrows). (C) T1-weighted, coronal section image of individual IV-5 at 12 years shows enlarged cerebellar folia and reduced volume indicating generalized (vermian and hemispheral) atrophy. Note also the mild cortical atrophy and visible sulci. (D) Cortical atrophy and white matter abnormal signals (arrows) demonstrated by FLAIR image of coronal section in the same individual. (E) Moderate cortical atrophy, very thin corpus callosum (arrow), and cerebellar atrophy (arrowhead) in a T1-weighted, sagital section of individual V-5 at 2.5 years. (F) FLAIR image, axial section of individual V-5 displaying frontal and temporal cortical atrophy compared with relatively preserved occipital cortex. The abnormal periventricular white matter signal (arrow) is consistent with dysmyelination.

Ten of our patients were homozygous to the previously reported c.336C>G founder mutation

Table S1. List of all variants in ACO2 and associated clinical phenotypes, population frequency, and in silico predictions for pathogenicity. Click here for additional data file. (37.8KB, xlsx)

Exon 3 c.336C>G r.(?) p.(Ser112Arg) Pathogenic (recessive) Aconitase 10 ACO2_000001 3,19,20