Aicardi-Goutières syndrome: differential diagnosis and aetiopathogenesis

Aicardi-Goutières syndrome (AGS) is a progressive encephalopathy with onset in the first year of life and a recessive autosomal pattern of inheritance. The syndrome is characterised by acquired microcephaly, basal ganglia calcifications, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis and raised interferon-alpha (INF-alpha) in the CSF. AGS is diagnosed on the basis of a clinical picture characterised by microcephaly and by the onset of encephalopathy associated with severe psychomotor delay, spasticity and extrapyramidal signs. CT is very important in the diagnosis of AGS, demonstrating clearly the presence of calcifications at basal ganglia level: these are often bilateral and symmetrical. CT scan and MRI reveal leukodystrophy and progressive cerebral atrophy. A raised level of INF-alpha in the CSF constitutes a marker of the syndrome: this level, which falls with age, is higher in the CSF than in the serum, suggesting intrathecal synthesis. Differential diagnosis in AGS is carried out to exclude the presence of other neurological and endocrinological pathologies characterised by the presence of intracranial calcification; considering the white matter abnormalities, it is necessary to exclude forms of leukodystrophy associated with metabolic defects, known or otherwise. One fundamental aspect that remains to be clarified is the aetiopathogenetic mechanism underlying AGS: the most well-founded hypotheses are reported. There does not exist, to date, any causal therapy for AGS, although genetic studies, particularly those focusing on interferon-regulating genes, may well provide some therapeutic indications.     

Atypical case of Aicardi-Goutières syndrome with late-onset myoclonic status.

Aicardi-Goutières syndrome (AGS) is a rare, progressive, autosomal recessive encephalopathy characterised by basal ganglia calcifications, chronic CSF lymphocytosis, and negative serological investigations for the common prenatal infections. The clinical profile is characterised by acquired microcephaly, mild to severe cognitive delay and dystonia. Epilepsy is usually not prominent. We report on a 19-year-old patient with an atypical clinical course, characterized by a relatively benign presentation at onset. Epilepsy with complex-focal seizures, possibly with a visual aura and sometimes with secondary generalization, started at the age of nine years. Clinical deterioration occurred later, and at the age of 17 years he experienced severe, generalized, myoclonic attacks lasting hours, which were partly controlled by the administration of piracetam.[Published with video sequences].     

Respiratory chain deficiency in a female with Aicardi-Goutières syndrome

Aicardi-Goutières syndrome (AGS) is an early-onset progressive encephalopathy characterized by calcifications of the basal ganglia, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level of CSF interferon (INF)-alpha. We report a female with mitochondrial respiratory chain deficiency fulfilling the criteria of AGS. Disease onset was in the first year of age with seizures and psychomotor regression. To date, at 4 years of age, she presents a severe encephalopathy, increased INF-alpha in the CSF, and calcifications of basal ganglia on computerized tomography. Cerebral magnetic resonance imaging showed bilateral and symmetric hypersignal of the posterior white matter. A complex I deficiency of the mitochondrial respiratory chain was found in skeletal muscle, which was associated with a complex IV deficiency in cultured skin fibroblasts. The question of whether this oxidative phosphorylation deficiency is primary or secondary in AGS is open to debate. We suggest giving consideration to systematic evaluation of the mitochondrial respiratory chain in skeletal muscle and skin fibroblasts of other AGS patients.     

Neurological findings in HIV-infected children: a review of 49 cases.

Many HIV-infected children have neurological involvement. We present our observations in 49 cases, 58% of which had some form of clinical neurological impairment. Most of the patients affected (71%) presented with progressive encephalopathy, characterized by developmental delay with loss of acquisitions and cognitive decline, an impaired growth curve, microcephaly and corticospinal dysfunction. CT-scan imaging shows cerebral atrophy in all cases and basal ganglia calcifications in 29%. Non-specific abnormalities are found on the EEG in two-thirds of cases and in the CSF in slightly less than half the cases. Pathological studies sometime revealed HIV encephalitis or lateral corticospinal tracts degeneration. Neurological impairment secondary to vascular events, neoplasms or opportunistic infections were rare, especially when compared with the adult HIV population.     

A case of progressive familial encephalopathy in infancy with calcification of the basal ganglia and chronic cerebrospinal fluid lymphocytosis

The authors report the ninth case of progressive familial encephalopathy in infancy, with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis, as recently described by Aicardi and Goutieres. The encephalopathy appears during the first year of life with bilateral spasticity, continuing microcephaly, abnormal eye movements, and a rapid course toward a behavioral vegetative state. In every case, there is a mild lymphocytosis in the CSF and brain atrophy with calcification of the lenticular nuclei. No evidence of an infectious disease has been discovered. This syndrome constitutes a distinct type of leukodystrophy, transmitted as an autosomal recessive trait. Our case is a reminder that the presence of CSF lymphocytosis in infants, with encephalopathy and calcification of the lenticular nuclei, may be due to genetic degenerative encephalopathy.     

Aicardi-Goutières syndrome

Aicardi-Goutieres syndrome is a familial progressive early onset encephalopathy with basal ganglia calcifications, chronic CSF lymphocytosis and high level of interferon-alpha in CSF. Cutaneous necrotic lesions and the neuropathological aspect of microangiopathy and microinfarctions suggest a vascular process in relation to elevated interferon-alpha. A genetic defect in the regulation of its synthesis may be the causal factor of the disorder.     

Aicardi-Goutieres syndrome: an oft unrecognised familial early-onset encephalopathy

INTRODUCTION: Aicardi-Goutieres syndrome, first described in 1984, is a progressive infantile familial encephalopathy featuring cerebral calcifications, mainly of the basal ganglia, cerebral white matter abnormalities and cerebrospinal fluid lymphocytosis. Most of the patients present with severe developmental retardation, microcephaly, abnormal eye movements, pyramidal tract signs, and prominent dystonic movements. An elevated level of interferon-alpha in the CSF is a constant feature, particularly during the first stages of the disease course. One locus has been mapped on chromosome 3p21 in about half of the families so far studied. PATIENTS: and results. We report two new French cases and discuss the limits of the clinical syndrome, the differential diagnosis and issues raised by the pathophysiological mechanisms involved. The major concern is to separate this condition from intrauterine infections because of the genetic and therapeutic consequences. A number of other questions remain unanswered. For example, we still do not know today at what age the absence of features like CSF lymphocytosis, and possibly absence of calcifications, rules out the diagnosis of the condition. The origin of the vasculitis lesions is not known, but seems to be related to dysregulation of interferon production and secretion. CONCLUSION: Currently about 75 patients have been reported, even though many more probably exist. The study of this syndrome can contribute to the understanding of some mechanisms of CNS calcification and in a broader perspective to that of chronic encephalopathies with dysregulation of immune mechanisms.     

Mitochondrial encephalopathy affecting only the central nervous system

A 32 year-old diabetic woman presented with an acute coma followed by epileptic seizures, aphasia and constructive apraxia. No ischemic lesion was demonstrated by CT scan and carotid angiograms. The other investigations showed sensorineural hearing loss, retinal degeneration, calcifications of the basal ganglia and lactic acidosis. The follow-up was marked by pseudo-dementia with personality disorders, memory deficits, behavioural changes, migrainous and epileptic features. Although there was no sign of muscular deficiency, a muscular biopsy showed characteristic ragged-red fibers and mitochondrial abnormalities at electron microscopy. The muscular biopsy enables us to classify this case as a mitochondrial encephalopathy similar to the MELAS syndrome. The stroke-like episodes are probably caused by a specific angiopathy involving the mitochondria of brain vessels.     

Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients

Familial idiopathic bilateral strio-pallido-dentate calcinosis is a rare autosomal dominant disorder characterized by massive symmetric calcification, detectable by CT, into the globus pallidus and striatum, with or without the involvement of the dentate nucleus, thalamus and white matter in the absence of alterations of calcium metabolism. Clinically, it has been associated with movement and/or neuropsychiatric disorders with age at onset typically in the fourth or fifth decade. Other sporadic or familial diseases can be responsible for brain calcifications with a similar anatomic strio-pallidal or strio-pallido-dentate pattern and, a restricted number of them, for neurological symptoms with onset in adulthood. Moreover, physiological age-related basal ganglia calcifications are often incidentally found, although with a far different CT aspect, in elderly patients with movement disorders. Indentifying familial and idiopathic cases may offer the opportunity to study the molecular mechanisms underlying this minerals deposition.     

Aicardi-Goutières syndrome: An update and results of interferon-α studies

Twenty-seven patients with familial encephalopathy with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis (Aicardi-Goutières syndrome) are reviewed. In 19 children, the onset was within the first 4 months of life. Most patients had normal head circumference at birth, but 21 developed microcephaly between 3 and 12 months. Neuroimaging showed severe and progressive brain atrophy in all patients. The extent and intensity of the calcification was variable even in the same sibship. CSF lymphocytosis persisted beyond 12 months of age in 7 children. High levels of interferon-α were found in serum and CSF in 14 patients. The higher CSF levels suggest intrathecal synthesis. Tubuloreticular inclusions related to the presence of interferon were found in 4 additional children. The 19 patients still alive (6 older than 10 years) are profoundly disabled. However, the syndrome may present with individual variations in severity, rapidity of evolution, and imaging features. Neuropathological examination in 2 patients failed to detect significant inflammatory lesions and showed only foci of necrosis and wide-spread demyelination. This study supports an autosomal recessive inheritance for this syndrome. The high level of interferon-α is not explained but may play a role in the pathogenesis of the disorder.     

Brain lactic alkalosis in Aicardi-Goutières syndrome

Aicardi-Goutières syndrome is a rare progressive encephalopathy characterized by acquired microcephaly, basal ganglia calcification, and chronic CSF lymphocytosis, raised levels of interferon alpha in CSF and plasma and chill-blain type lesions. A possible mechanism of injury is cytokine related microangiopathy. We report brain imaging and proton (1H) and phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) findings during the first year after birth in two patients. In patient 1 the evolution of brain metabolite ratios and intracellular pH obtained from serial 1H (long TE) and 31P MRS studies are described; in patient 2 a single 1H (short TE) MRS study is described. Imaging findings included basal ganglia calcifications, cerebral atrophy, and leukodystrophy. The MRS results demonstrated that Aicardi-Goutières syndrome is associated with reduced NAA/Cr, reflecting decreased neuronal/axonal density or viability, increased myo-inositol/Cr, reflecting gliosis or osmotic stress and a persisting brain lactic alkalosis. A brain lactic alkalosis has also been observed in those infants surviving perinatal hypoxia-ischaemia but with a poor neurodevelopmental outcome. A possible mechanism leading to brain alkalosis is up-regulation of the Na+/H+ transporter by focal areas of ischaemia related to the microangiopathy or by pro-inflammatory cytokines. Such brain alkalosis may be detrimental to cell survival and may increase glycolytic rate in astrocytes leading to an increased production of lactate.     

Familial idiopathic cerebral calcifications.

Nine members of a family spanning three generations showed bilateral calcifications of the basal ganglia with autosomal dominant inheritance. Two members developed chorea, dementia, and a characteristic speech disturbance (palialalia) in the third or fourth decade. A third member possibly shows the initial stage of a similar syndrome. Six members with calcifications but without neurological signs are younger than 25 years. All nine patients had normal calcium and phosphorus, and no evidence of endocrinological or somatic abnormalities. Thie 'isiopathic' picture must be differentiated from hypoparathyroidism and pseudohypoparathyroidism.     

Case of Aicardi-Goutières syndrome with long-lasting increase of cerebrospinal interferon-alpha

Aicardi-Goutières syndrome is a rare progressive encephalopathy characterized by a typical clinical picture, bilateral basal ganglia calcifications, leukodystrophy and brain atrophy, lymphocytosis, and elevated interferon-alpha in the cerebrospinal fluid. Among the cases described to date, variability in the clinical expression or in the cerebrospinal fluid abnormalities has been reported. We present a case with a delayed diagnosis at the age of 8 years, when brain computed tomography was done because there was no first image from the age of 8 months, when the disease started. Symmetric basal ganglia calcifications were visualized and led to purposeful investigation of the cerebrospinal fluid. It revealed an interferon-alpha titer of 103 IU/mL, which, together with the progressive brain damage and disease course, was crucial for the diagnosis. This rare finding of long-term highly elevated interferon-alpha in the cerebrospinal fluid is discussed with respect to the clinical course.     

The Aicardi-Goutières syndrome: Variable clinical expression in two siblings

We report 2 siblings with the Aicardi-Goutières syndrome (encephalopathy, basal ganglia calcifications, and persistent cerebrospinal fluid pleiocytosis). The eldest sibling is severely retarded; his younger brother has only mild, slowly progressive neurological deficits. To our knowledge, such a striking difference in clinical expression has not been reported previously.     

Aicardi-Goutières syndrome: a genetic microangiopathy?

Aicardi-Goutières syndrome (AGS) (McKusick 225750) is an autosomal recessive disease with onset in the 1st year of life, resulting in progressive microcephaly, calcification of cerebral white matter, thalamus and basal ganglia, generalized cerebral demyelination and a chronic low-grade CSF lymphocytosis, without evidence of infection. We report the autopsy of a patient who died with this disorder at the age of 17 years. Findings were severe microencephaly, diffuse but inhomogeneous cerebral white matter loss with associated astrocytosis, calcific deposits in the white matter, thalami and basal ganglia. Neocortex and cerebellar cortex were affected by wedge-shaped microinfarctions. Small vessels showed calcification in the media, adventitia and perivascular spaces. These findings are similar to some previous publications that in retrospect may have been AGS, but this is the first reported cerebral microangiopathy in which the diagnosis AGS was made during lifetime. This report provides evidence that microangiopathy plays a significant role in the pathogenesis of AGS. Received: 28 October 1998 / Revised, accepted: 8 January 1999     

Pontocerebellar hypoplasia associated with respiratory-chain defects.

Pontocerebellar hypoplasias are congenital disorders of brain morphogenesis which include such diverse etiologies as carbohydrate-deficient glycoprotein syndrome type 1, cerebromuscular dystrophies (Walker-Warburg syndrome, Fukuyama syndrome, muscle-eye-brain disease) and at least two types of autosomal recessive neurodegenerations known as pontocerebellar hypoplasia type I and II. Pontocerebellar hypoplasia type 1 is a lethal phenotype and clinical features include congenital contractures, respiratory insufficiency, central and peripheral motor dysfunction and spinal anterior horn degeneration. Type 2 is characterized by progressive microcephaly, extrapyramidal dyskinesia and normal spinal cord findings. In this paper, we describe a girl, born at 33 weeks of gestation, presenting with respiratory insufficiency and multiple contractures. MRI scan of the brain demonstrated pontocerebellar hypoplasia and cortical and diffuse periventricular white matter abnormalities. Postmortem examination showed pontocerebellar hypoplasia with extensive gliosis of the periventricular white matter and of the basal ganglia with normal spinal cord findings. Histology of skeletal muscle was normal. Biochemical analysis demonstrated multiple deficiencies of respiratory chain enzymes in skin fibroblasts. This case demonstrates a lethal phenotype of pontocerebellar hypoplasia without spinal cord abnormalities associated with a respiratory-chain disorder. The diagnostic workup in a patient whose brain image shows pontocerebellar hypoplasia should include a search for respiratory-chain impairment.     

Infantile familial encephalopathy with cerebral calcifications and leukodystrophy

Two sets of siblings, in two different families, presenting with congenital and progressive neurological disorders, cerebral calcifications and leukodystrophy are reported. In the first family, the diagnosis of brain calcifications in two infants was based on skull X-rays; in the second family, ultrasound scans showed hyperechoic areas in the basal ganglia and periventricular white matter in both infants. Neuropathological studies confirmed the calcifications and revealed severe abnormalities of the white matter with GFAP positive gliosis. Electron micrographs showed large astrocytes with an increased amount of glial filaments. In the group of idiopathic non arteriosclerotic cerebral calcifications, these four cases may represent a separate entity with possible autosomal recessive inheritance.     

Cockayne syndrome: unusual neuropathological findings and review of the literature.

Two siblings with Cockayne syndrome (CS) are described and the literature on the subject is briefly reviewed. Of particular interest were the unusual neuropathological findings in 1 of the patients. These included microcephaly, white matter atrophy with patchy loss of myelinated fibers, calcifications of the basal ganglia, occasional ferrugination of cerebral and cerebellar neurons, and severe cerebellar degeneration. Findings not previously reported in CS were proliferation of extremely bizarre astrocytes, neurofibrillary tnagles, and pigmentation of the globus pallidus. We conclude that brain involvement in CS is a result of primary degeneration in the central nervous system rather than being secondary to angiopathy or normal pressure hydrocephalus, as previously suggested.     

Autosomal recessive ataxia, slow eye movements, dementia and extrapyramidal disturbances

An Arab family with an autosomal recessive form of spinocerebellar degeneration with slow eye movements is reported. Hitherto all the reported cases were either sporadic or of autosomal dominant inheritance. Associated are progressive intellectual impairment and extrapyramidal dysfunction as well as peripheral neuropathy and skeletal abnormalities. Muscle biopsy revealed non-specific mitochondrial abnormalities. The spectrum of eye movement abnormalities is discussed and the literature is reviewed. It is concluded that the hallmark of this syndrome (slow or even absent saccades) is one of a group of oculomotor abnormalities, all being characterized by delayed initiation and slow velocity. The syndrome seems to be related to the olivopontocerebellar degenerations, but differs in that there is in addition selective degeneration of certain tracts and nuclei in the mesencephalon and probably more rostral structures.     

Muscle involvement in the cerebro-oculo-facio-skeletal syndrome

We report a 14-year-old male, born to consanguineous parents, with microcephaly, intracranial calcification, severe mental retardation, cataracts, optic atrophy, pigmentary retinopathy, contractures, scoliosis, and failure to thrive. His brain imaging revealed extensive basal ganglia calcifications. He has normal ultraviolet sensitivity. These features are consistent with the autosomal recessive cerebro-oculo-facio-skeletal syndrome. In addition, he has severe muscle weakness with end-stage muscle changes on biopsy. There have been few reports of muscle involvement in cerebro-oculo-facio-skeletal syndrome, and this is the first time it has been described in a cerebro-oculo-facio-skeletal patient with normal ultraviolet sensitivity. This case extends the extensive phenotypic similarities between cerebro-oculo-facio-skeletal syndrome patients with and without abnormal ultraviolet sensitivity, and highlights the cerebro-oculo-facio-skeletal syndrome in the differential diagnosis of congenital muscular dystrophies.