A 5 1/2 year old boy at 3 1/2 years began losing lower extremity strength, initially on the right but then bilaterally. Initially, there also seemed to be involvement of right upper extremity and right sided hyperreflexia. He gradually lost his ability to ambulate independently. There was also loss of verbalization. Currently, the deep tendon reflexes are brisk diffusely and motor tone is increased diffusely.
He had an autism/ID Xpanded panel done through GeneDx. This showed a variant of unknown significance in the LAS1L gene. He also had a cerebral palsy spectrum disorder panel of genetic testing done, which showed a variant of unknown significance in the IFIH1 gene [c.2644A>C (p.Met882Leu)] This variant had been detected on an earlier autism/ID panel, which was performed as a trio of tests with both of his parents. His father had the same variant, causing the autism/ID panel not to report it on the initial findings. Whole genome sequencing was nondiagnostic. Some of the previously identified VUS were re-demonstrated. Cerebrospinal fluid studies were also unremarkable, except for an increased CSF neopterin of 123 (normal 7 to 65). A repeat neopterin was 43 (7-40). Extensive additional laboratory studies were unrevealing.
The IFIH1 gene is associated with Aicardi-Goutieres syndrome type 7. There has been speculation that this, indeed, is the disorder the patient has.
Images from the most recent brain MRI are below. The axial and coronal are T2 and the sagittal T1. Aside from the thinning of the posterior corpus callosum, no abnormality was described.
Uggetti C, La Piana R, Orcesi S, Egitto MG, Crow YJ, Fazzi E. Aicardi-Goutieres syndrome: neuroradiologic findings and follow-up. AJNR Am J Neuroradiol. 2009 Nov;30(10):1971-6. doi: 10.3174/ajnr.A1694. Epub 2009 Jul 23. PMID: 19628626; PMCID: PMC7051307.
Abstract
Background and purpose: To date, few studies have focused specifically on imaging findings in Aicardi-Goutières syndrome (AGS). We set out to evaluate retrospectively neuroradiologic data from a large sample of patients with AGS, focusing on the pattern of white matter abnormalities and the temporal evolution of the cerebral involvement to establish the radiologic natural history of the disease.
Materials and methods: Thirty-six patients, 18 girls and 18 boys, were included. All had a clinical diagnosis of AGS, genetically confirmed in 31 of them. For every subject, we reviewed at least 1 CT and 1 MR imaging study; 19 (52.7%) had multiple examinations. In all, we reviewed 109 examinations. Clinical-neuroradiologic comparisons were analyzed by using the chi(2) test.
Results: Calcifications were found in all subjects, mainly in the basal ganglia, lobar white matter, and dentate nuclei. Abnormal white matter was present in all the subjects, showing 2 patterns of distribution: diffuse in 18 (50%) and an anteroposterior gradient in 18 (50%). Cystic areas were observed in the temporal and/or frontal lobes in 12/36 patients (33.3%). A correlation was found between early age at onset and severity of the leukoencephalopathy in the frontal (P = .024) and temporal (P = .034) regions. A significant degree of cerebral atrophy was found in 31/36 subjects (86.1%). The neuroradiologic presentation remained substantially stable with time.
Conclusions: The different neuroradiologic presentations of AGS are here outlined for the first time in a large sample of patients. These findings may facilitate more precise and earlier diagnosis of this rare but probably underdiagnosed syndrome.
Han VX, Mohammad SS, Jones HF, Bandodkar S, Crow YJ, Dale RC; AGS-JAKi Study Group. Cerebrospinal fluid neopterin as a biomarker of treatment response to Janus kinase inhibition in Aicardi-Goutières syndrome. Dev Med Child Neurol. 2022 Feb;64(2):266-271. doi: 10.1111/dmcn.15025. Epub 2021 Aug 20. PMID: 34415581.
Abstract
Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutières syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range -36% to -88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range -63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response.
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ReplyDeleteHave you done EMG to look for a neuropathy? You might want to consider an acquired disorder on top of autism for example which can be difficult but certainly sounds like a neurodegenerative one with both UMN and LMN findings and hardly any significant brain MRI visible findings.
There are some disorders such as Friedreich Ataxia syndrome that would be missed on WES and potentially WGS since it is due to repeat expansion. EMG would show a demyelinating sensory predominant neuropathy (wipe of all sensory nerve responses and slowing of motor nerve responses) for example.
If the EMG is abnormal, you could test for frataxin enzyme level (Mayo test) and consider neuromuscular gene panel testing which may pick up a dup/del paired with a point mutation that would be missed on WES as well since you are more specific with panel testing than with exome. I am actually surprised and impressed you were able to get whole genome done clinically but alas, this was not helpful.
As for Aicardi-Goutierres, has a head CT been done? I don't see GRE sequencies on your MRI samples which might pick up on calcifications. AG may have basal ganglia calcifications as you might be aware but I'm not sure if this variant is associated with calcifications nor when/how often you see it. The CHOP leukodystrophy folks might be better informed of the AGS findings since one of my patients go there and is getting some sort of clinical trial treatment. The elevated neopterin is so non-specific but I agree is seen in AGS as well as inflammatory disorders. (continued)