{"id":8519,"date":"2026-08-13T20:16:50","date_gmt":"2026-08-13T20:16:50","guid":{"rendered":"https:\/\/neuropediatoolkit.org\/?p=8519"},"modified":"2026-08-15T12:13:54","modified_gmt":"2026-08-15T12:13:54","slug":"sindromes-cerebro-renales","status":"publish","type":"post","link":"https:\/\/neuropediatoolkit.org\/en\/sindromes-cerebro-renales\/","title":{"rendered":"Cerebro-renal syndromes."},"content":{"rendered":"<h3 class=\"wp-block-heading\">Introduction<\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Cerebro-renal syndromes constitute a heterogeneous group of entities in which central nervous system involvement and renal dysfunction coexist, either due to a common pathophysiological mechanism (defect of a metabolic pathway that affects both organs) or due to the pleiotropic expression of a gene that is critically expressed in the brain and kidney (typically at the ciliary level). Distinguishing between both groups is clinically relevant because it guides the complementary study, prognosis and genetic counseling.<\/p>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h3 class=\"wp-block-heading\">1. Cerebro-renal syndromes of metabolic cause<\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">In this group, kidney involvement is usually <strong>tubular<\/strong> (with Fanconi-type patterns or tubular acidosis) and neurological involvement usually includes hypotonia, epilepsy (often of early onset, including infantile spasms) and developmental delay. The common mechanism is usually a defect in an essential biochemical pathway (oxidative phosphorylation, glycosylation, peroxisomal \u03b2-oxidation, amino acid\/cystine transport) that simultaneously compromises tissues with high energy demand or intense protein turnover, such as the renal proximal tubule and the nervous system.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\">1.1 Mitochondrial diseases<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: defects of the mitochondrial respiratory chain (complexes I-V), depletion or mutations of mitochondrial DNA.<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: Fanconi type proximal tubulopathy (normoglycemic glycosuria, phosphaturia, generalized aminoaciduria, proximal tubular acidosis).<\/li>\n\n\n\n<li><strong>Neurological involvement<\/strong>: hypotonia, epilepsy (including infantile spasms), developmental regression, basal ganglia\/trunk involvement (Leigh syndrome) in cases with a structural pattern.<\/li>\n\n\n\n<li><strong>Diagnostic keys<\/strong>: elevated lactate\/pyruvate (blood, CSF), although they may be normal in early stages; Brain MRI with Leigh pattern (not always present); muscle biopsy; mitochondrial genetic panel.<\/li>\n\n\n\n<li><strong>Differential metabolic diagnosis:<\/strong> Elevated lactate\/pyruvate ratio (&gt;20-25, suggests respiratory chain defect, unlike a normal ratio with elevated lactate, which points more to a pyruvate dehydrogenase defect or gluconeogenesis). Plasma amino acids: elevated alanine (indirect reflection of sustained lactacidemia). Organic acids in urine: may show elevated Krebs cycle intermediates (fumaric, malic) and 3-methylglutaconic acid in specific subtypes. Ketone bodies usually normal or slightly elevated, without the marked ketosis pattern of classic organic acidemias.<\/li>\n\n\n\n<li><strong>Important teaching point<\/strong>: both normal lactate and normal MR <strong>they do not rule out<\/strong> mitochondrial disease, especially in young or early infants.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">1.2 Congenital disorders of glycosylation (CDG)<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: defects in protein glycosylation (N-glycosylation, type I, or processing, type II). The most common subtype is <strong>PMM2-CDG<\/strong> (formerly CDG-Ia).<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: tubular proteinuria, some degree of tubular dysfunction in some subtypes; less florid than in classic Fanconi.<\/li>\n\n\n\n<li><strong>Neurological involvement<\/strong>: early severe hypotonia (often the presenting sign), epilepsy, marked failure to thrive, strabismus, cerebellar atrophy (often later onset\/progressive, so initial MRI may be normal).<\/li>\n\n\n\n<li><strong>Associated multisystem involvement<\/strong>: coagulopathy (\u2193antithrombin III, protein C\/S), liver disease, pericardial effusion, subtle dysmorphic features (inverted nipples, abnormal gluteal\/suprapubic fat distribution).<\/li>\n\n\n\n<li><strong>Differential metabolic diagnosis:<\/strong> The \u201cfirst-line\u201d metabolic profile (urine organic acids, plasma amino acids, ammonium, lactic) is usually <strong>normal<\/strong>, which in itself is a guiding fact \u2014 an infant with severe hypotonia, multisystem involvement and a normal basic metabolic study should suggest CDG. Nonspecific hypoglycemia and hypertransaminasemia may occur. The specific finding is isoelectrofocusing of transferrin (type I pattern: increase in asialo- and disialotransferrin isoforms).<\/li>\n\n\n\n<li><strong>Important teaching point<\/strong>: Normal brain MRI in the young infant is compatible with CDG, since cerebellar atrophy is usually an evolutionary finding, not necessarily present in the first weeks of life.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">1.3 Peroxisomal disorders \u2014 Zellweger spectrum<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: defect in peroxisomal biogenesis (genes <em>PEX<\/em>), with accumulation of very long chain fatty acids (VLCFA) and deficit of peroxisomal functions.<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: predominate <strong>renal cortical cysts<\/strong>, rather than a florid resorptive tubulopathy (as opposed to mitochondrial\/Lowe).<\/li>\n\n\n\n<li><strong>Neurological involvement<\/strong>: very severe hypotonia from birth (one of the most severe in this group of entities), early seizures (including infantile spasms), alterations in neuronal migration on MRI (polymicrogyria, pachygyria).<\/li>\n\n\n\n<li><strong>Associated traits<\/strong>: characteristic facial dysmorphia (prominent forehead, wide fontanels, epicanthus, hypertelorism), hepatomegaly with liver dysfunction\/cholestasis, ocular disorders (cataracts, pigmentary retinopathy, glaucoma).<\/li>\n\n\n\n<li><strong>Differential metabolic diagnosis:<\/strong> In addition to elevated VLCFA (C26:0 and C24:0\/C22:0 ratio, C26:0\/C22:0 elevated), the complete peroxisomal profile shows elevated phytanic and pristanic acids, elevated pipecolic acid in plasma, and erythrocyte plasmalogens. <strong>descended<\/strong> (This last piece of information is especially useful as a rapid screening, since its synthesis depends on peroxisomal function). The \"standard\" metabolic study (organic acids, amino acids, ammonium) is usually normal, similar to CDG.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">1.4 Lowe syndrome (oculocerebrorenal)<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: mutations in <em>OCRL1<\/em>, X-linked inheritance (practically exclusive to men).<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: Fanconi-type proximal tubulopathy, although <strong>typically appearing somewhat later<\/strong> (3-12 months) than in mitochondrial.<\/li>\n\n\n\n<li><strong>Neurological involvement<\/strong>: severe neonatal hypotonia (\"floppy baby\"), seizures in about half of cases, intellectual disability (evident later).<\/li>\n\n\n\n<li><strong>Key Discriminant Trait<\/strong>: <strong>bilateral congenital cataracts, practically constant (&gt;95-100%)<\/strong>, present from birth and detectable with ophthalmological examination with pupillary dilation. It may be associated with glaucoma (~50%).<\/li>\n\n\n\n<li><strong>Differential metabolic diagnosis:<\/strong> The urinary pattern is that of a non-specific generalized Fanconi (generalized aminoaciduria, glycosuria with normal blood glucose, phosphaturia, bicarbonaturia), without a plasma or organic acid\/amino acid biochemical marker specific to the entity \u2014 unlike the others, here the \u201cmetabolic diagnostic gap\u201d is closed with the ocular symptoms (cataracts) plus the genetic\/enzymatic study (activity of the phosphatidylinositol-4,5-bisphosphate 5-phosphatase of OCRL in fibroblasts), not with a discriminating metabolic profile.<\/li>\n\n\n\n<li><strong>Important teaching point<\/strong>: A normal ophthalmological examination with pupillary dilation makes Lowe's diagnosis very unlikely, given the constant ocular finding.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">1.5 Nephropathic cystinosis<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: mutations in <em>CTNS<\/em>, lysosomal accumulation of cystine.<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: complete Fanconi syndrome, typically appearing somewhat later (6-12 months) than in the previous entities.<\/li>\n\n\n\n<li><strong>Neurological involvement<\/strong>: in the classic form, neurological involvement is less prominent in the infant stage and develops later (progressive cognitive impairment, motor alterations).<\/li>\n\n\n\n<li><strong>Differential metabolic diagnosis:<\/strong> Elevated intraleukocyte cystine (&gt;2 nmol hemicystin\/mg protein) is the specific diagnostic test. The rest of the metabolic profile (organic acids, plasma amino acids, ammonium) is normal \u2014 the aminoaciduria is generalized but of tubular origin (secondary Fanconi), not a primary disorder of amino acid metabolism.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">1.6 Classic galactosemia (GALT deficiency)<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism:<\/strong> galactose-1-phosphate uridyltransferase (GALT) deficiency, with toxic accumulation of galactose-1-phosphate and galactitol in the liver, kidney, lens, and nervous system.<\/li>\n\n\n\n<li><strong>Kidney involvement:<\/strong> Fanconi syndrome (proximal tubulopathy) due to direct toxicity of galactose-1-phosphate accumulated in the proximal tubule.<\/li>\n\n\n\n<li><strong>Neurological involvement:<\/strong> in the acute neonatal phase (after starting lactose lactation) \u2014 lethargy, hypotonia, feeding refusal, vomiting; increased risk of fulminant sepsis <em>E.coli<\/em> (galactose-1-phosphate inhibits leukocyte function). In the long term, despite a strict galactose-free diet: mild-moderate intellectual disability, verbal dyspraxia, ataxia, and primary ovarian failure in girls.<\/li>\n\n\n\n<li><strong>Associated traits:<\/strong> cholestatic jaundice and hepatomegaly with progression to cirrhosis if untreated; cataracts due to galactitol accumulation (\u201coil drop\u201d); coagulopathy.<\/li>\n\n\n\n<li><strong>Differential metabolic diagnosis:<\/strong> The classic finding with high diagnostic yield is <strong>dissociation between positive reducing substances in urine and negative glycosuria<\/strong> (glucose-oxidase test strip, specific for glucose, negative; Benedict\/Clinitest test, which detects any reducing sugar including galactose, positive). This dissociation is practically pathognomonic as long as the infant receives lactose in the diet and is lost if it has already been withdrawn. It is confirmed with elevated erythrocyte galactose-1-phosphate and absent or greatly reduced erythrocyte GALT activity. The rest of the basic metabolic profile (organic acids, amino acids, ammonium) is characteristically normal, which helps differentiate it from organic acidemias or urea cycle defects in a septic\/vomiting neonate.<\/li>\n\n\n\n<li><strong>Important teaching point:<\/strong> The key data to differentiate it clinically from other entities in the group is the <strong>temporal relationship with the introduction of breastfeeding<\/strong> \u2014 symptoms emerge after starting lactose feeding (breast milk or standard formula) and improve when it is withdrawn. Cataracts may be the first detectable sign and are included in the differential diagnosis of Lowe's, but unlike these (congenital and fixed), those of galactosemia appear later and <strong>partially reversible<\/strong> if the galactose-free diet is established early. <\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">1.7 Other entities to consider in the metabolic differential: <\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Organic acidemias<\/strong> (methylmalonic, propionic): metabolic acidosis with elevated anion gap (unlike tubulopathies, which present with normal AG), hyperammonemia, ketosis.<\/li>\n\n\n\n<li><strong>Urea cycle defects<\/strong>: hyperammonemia as the dominant finding, without typical metabolic acidosis or tubulopathy.<\/li>\n\n\n\n<li><strong>Fabry disease<\/strong> (late phase): progressive nephropathy and CNS involvement (stroke), although presenting much later than the rest of this group.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h3 class=\"wp-block-heading\">2. Cerebro-renal syndromes of genetic\/structural cause (ciliopathies and related diseases)<\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">In this group, the pathophysiological link between brain and kidney is not a shared metabolic pathway, but the <strong>expression of the gene product in the primary cilium or related structures<\/strong>, present in both renal tubular cells and the ependyma, photoreceptors and other structures of the CNS. Kidney involvement is usually <strong>structural<\/strong> (cysts, dysplasia) rather than tubular\/resorptive, and is frequently associated with involvement of other organs with cilia (retina, liver, skeleton).<\/p>\n\n\n\n<h4 class=\"wp-block-heading\">2.1 Bardet-Biedl syndrome<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: ciliopathy, autosomal recessive inheritance (oligogenic in some cases), multiple genes <em>BBS<\/em> involved.<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: variable structural anomalies \u2014 dysplasia, cysts, calyceal malformations; It can progress to chronic kidney disease.<\/li>\n\n\n\n<li><strong>Neurological involvement\/other systems<\/strong>: variable intellectual disability, pigmentary retinopathy (usually the earliest and most characteristic finding), postaxial polydactyly, childhood-onset obesity, hypogonadism.<\/li>\n\n\n\n<li><strong>Diagnostic keys<\/strong>: the combination of polydactyly + pigmentary retinopathy + obesity + kidney anomalies in a child strongly guides the diagnosis; genetic confirmation.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">2.2 Joubert syndrome<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: ciliopathy, with the characteristic \u201cmolar tooth sign\u201d on MRI (vermian hypoplasia with alteration of the superior cerebellar peduncles).<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: nephronophthisis in a relevant subgroup of patients (medullary cystic nephropathy, progression to renal failure).<\/li>\n\n\n\n<li><strong>Neurological involvement<\/strong>: marked hypotonia, ataxia, abnormal respiratory pattern (episodes of alternating tachypnea\/apnea) characteristic of the neonatal period, developmental delay.<\/li>\n\n\n\n<li><strong>Other associated findings<\/strong>: retinal coloboma, liver involvement (congenital hepatic fibrosis) in overlapping forms.<\/li>\n\n\n\n<li><strong>Diagnostic keys<\/strong>: The molar tooth sign on MRI is practically diagnostic; genetic panel study of ciliopathies.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">2.3 Isolated nephronophthisis and related syndromes (Senior-L\u00f8ken)<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Mechanism<\/strong>: predominant renal ciliopathy, with associated retinal involvement in Senior-L\u00f8ken syndrome (nephronophthisis + pigmentary retinopathy\/Leber congenital amaurosis).<\/li>\n\n\n\n<li><strong>Kidney involvement<\/strong>: progressive medullary cystic nephropathy, polyuria\/polydipsia due to a lack of urinary concentration as a frequent initial sign, evolution to terminal renal failure in adolescence in the juvenile form.<\/li>\n\n\n\n<li><strong>Neurological involvement<\/strong>: in pure forms, neurological involvement is less prominent than in Joubert or Bardet-Biedl; There may be ataxia in forms with cerebellar overlap.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">2.4 Polycystic kidney disease and CNS involvement<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Autosomal recessive polycystic disease (ARPKD, <em>PKHD1<\/em>)<\/strong>: massive bilateral cystic kidney involvement, associated congenital liver fibrosis; Direct neurological involvement is less characteristic than in previous ciliopathies, although there may be associated hypertension with secondary repercussions.<\/li>\n\n\n\n<li><strong>Autosomal dominant polycystic disease (ADPKD)<\/strong>: It is relevant to mention the association with intracranial aneurysms (although they occur in adults, not in infants).<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">2.5 Other ciliopathies with cerebro-renal involvement<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Meckel-Gruber syndrome<\/strong>: lethal form of the spectrum of ciliopathies, with occipital encephalocele, massive cystic renal dysplasia and polydactyly; incompatible with life beyond the neonatal period in most cases.<\/li>\n\n\n\n<li><strong>Asphyxiating thoracic dysplasia (Jeune) and related ciliopathic skeletal syndromes<\/strong>: cystic renal involvement\/nephronophthisis associated with thoracic skeletal dysplasia; The neurological involvement is secondary (hypoxia due to restrictive respiratory failure) rather than primary.<\/li>\n<\/ul>","protected":false},"excerpt":{"rendered":"<p>Introduction Cerebro-renal syndromes constitute a heterogeneous group of entities in which central nervous system involvement and renal dysfunction coexist, either due to a common pathophysiological mechanism (defect of a metabolic pathway that affects both organs) or due to the pleiotropic expression of a gene that is critically expressed in the brain... <\/p>\n<p class=\"link-more\"><a href=\"https:\/\/neuropediatoolkit.org\/en\/sindromes-cerebro-renales\/\" class=\"more-link\">Continue reading<span class=\"screen-reader-text\"> \u00abCerebro-renal syndromes.\u00bb<\/span><\/a><\/p>","protected":false},"author":1,"featured_media":8524,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_themeisle_gutenberg_block_has_review":false,"footnotes":""},"categories":[7],"tags":[],"class_list":["post-8519","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-metabolismo","entry"],"_links":{"self":[{"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/posts\/8519","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/comments?post=8519"}],"version-history":[{"count":6,"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/posts\/8519\/revisions"}],"predecessor-version":[{"id":8532,"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/posts\/8519\/revisions\/8532"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/media\/8524"}],"wp:attachment":[{"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/media?parent=8519"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/categories?post=8519"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/neuropediatoolkit.org\/en\/wp-json\/wp\/v2\/tags?post=8519"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}